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Meng XM, Wang L, Nikolic-Paterson DJ, Lan HY. Innate immune cells in acute and chronic kidney disease. Nat Rev Nephrol 2025:10.1038/s41581-025-00958-x. [PMID: 40263532 DOI: 10.1038/s41581-025-00958-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/24/2025]
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are inter-related clinical and pathophysiological disorders. Cells of the innate immune system, such as granulocytes and macrophages, can induce AKI through the secretion of pro-inflammatory mediators such as cytokines, chemokines and enzymes, and the release of extracellular traps. In addition, macrophages and dendritic cells can drive the progression of CKD through a wide range of pro-inflammatory and pro-fibrotic mechanisms, and by regulation of the adaptive immune response. However, innate immune cells can also promote kidney repair after acute injury. These actions highlight the multifaceted nature of the way by which innate immune cells respond to signals within the kidney microenvironment, including interaction with the complement and coagulation cascades, cells of the adaptive immune system, intrinsic renal cells and infiltrating mesenchymal cells. The factors and mechanisms that underpin the ability of innate immune cells to contribute to renal injury or repair and to drive the progression of CKD are of great interest for understanding disease processes and for developing new therapeutic approaches to limit AKI and the AKI-to-CKD transition.
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Affiliation(s)
- Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - David J Nikolic-Paterson
- Department of Nephrology, Monash Medical Centre and Monash University Centre for Inflammatory Diseases, Melbourne, Victoria, Australia
| | - Hui-Yao Lan
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
- Departments of Medicine & Therapeutics, the Chinese University of Hong Kong, Hong Kong, and Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China.
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Christa M, Dennis F, Philip R, Jakob L, Timo S. Admission glucose, HbA1c levels and inflammatory cytokines in patients with acute ST-elevation myocardial infarction. Clin Proteomics 2025; 22:8. [PMID: 39962379 PMCID: PMC11834255 DOI: 10.1186/s12014-025-09530-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 02/04/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND To investigate the association between admission glucose and HbA1c values and inflammatory plasma proteins in hospitalized patients with acute ST-elevation myocardial infarction (STEMI). METHODS This analysis was based on 345 STEMI patients recorded by the population-based Myocardial Infarction Registry Augsburg between 2009 and 2013. Using the OLINK inflammatory panel, a total of 92 protein biomarkers were measured in arterial blood samples, which were obtained within the scope of cardiac catheterization immediately after admission. The associations between admission glucose and HbA1c levels and the 92 protein markers were investigated using multivariable linear regression models. RESULTS Admission glucose showed significantly positive associations with the inflammatory markers IL-10, IL-8, IL-6, FGF-21, IL-7, ST1A1, MCP-1, 4E-BP1, SIRT2, STAMBP and IL-18R1 after Bonferroni adjustment. HbA1c values were only significantly associated with IL-18R1. In stratified analyses, admission glucose was not significantly associated with any plasma protein in the diabetes subgroup, while there were several protein markers that showed significantly positive associations with admission glucose in STEMI patients without known diabetes, namely IL-10, CCL20, IL-8, MCP-1 and IL-6. CONCLUSIONS Admission glucose in patients hospitalized due to an acute STEMI seems to be related to an inflammatory and immune-related response, expressed by an increase in inflammation-related plasma proteins in particular in non-diabetic patients with stress hyperglycemia. The present results may open new avenues for the development of biomarkers suitable as potential diagnostic or prognostic clinical markers.
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Affiliation(s)
- Meisinger Christa
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156, Augsburg, Germany.
| | - Freuer Dennis
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156, Augsburg, Germany
| | - Raake Philip
- Department of Cardiology, Respiratory Medicine and Intensive Care, University Hospital Augsburg, Stenglinstraße 2, 86156, Augsburg, Germany
| | - Linseisen Jakob
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156, Augsburg, Germany
| | - Schmitz Timo
- Epidemiology, Medical Faculty, University of Augsburg, University Hospital Augsburg, Stenglinstraße 2, 86156, Augsburg, Germany
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Sunilkumar S, Subrahmanian SM, Yerlikaya EI, Toro AL, Harhaj EW, Kimball SR, Dennis MD. REDD1 expression in podocytes facilitates renal inflammation and pyroptosis in streptozotocin-induced diabetic nephropathy. Cell Death Dis 2025; 16:79. [PMID: 39920111 PMCID: PMC11806006 DOI: 10.1038/s41419-025-07396-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 01/10/2025] [Accepted: 01/27/2025] [Indexed: 02/09/2025]
Abstract
Sterile inflammation resulting in an altered immune response is a key determinant of renal injury in diabetic nephropathy (DN). In this investigation, we evaluated the hypothesis that hyperglycemic conditions augment the pro-inflammatory immune response in the kidney by promoting podocyte-specific expression of the stress response protein regulated in development and DNA damage response 1 (REDD1). In support of the hypothesis, streptozotocin (STZ)-induced diabetes increased REDD1 protein abundance in the kidney concomitant with renal immune cell infiltration. In diabetic mice, administration of the SGLT2 inhibitor dapagliflozin was followed by reductions in blood glucose concentration, renal REDD1 protein abundance, and immune cell infiltration. In contrast with diabetic REDD1+/+ mice, diabetic REDD1-/- mice did not exhibit albuminuria, increased pro-inflammatory factors, or renal macrophage infiltration. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1-dependent activation of NF-κB signaling. REDD1 deletion in podocytes attenuated both the increase in chemokine expression and macrophage chemotaxis under hyperglycemic conditions. Notably, podocyte-specific REDD1 deletion prevented the pro-inflammatory immune cell infiltration in the kidneys of diabetic mice. Furthermore, exposure of podocytes to hyperglycemic conditions promoted REDD1-dependent pyroptotic cell death, evidenced by an NLRP3-mediated increase in caspase-1 activity and LDH release. REDD1 expression in podocytes was also required for an increase in pyroptosis markers in the glomeruli of diabetic mice. The data support that podocyte-specific REDD1 is necessary for chronic NF-κB activation in the context of diabetes and raises the prospect that therapies targeting podocyte-specific REDD1 may be helpful in DN.
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Affiliation(s)
- Siddharth Sunilkumar
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
| | - Sandeep M Subrahmanian
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
| | - Esma I Yerlikaya
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
| | - Allyson L Toro
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
| | - Edward W Harhaj
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, USA
| | - Scot R Kimball
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
| | - Michael D Dennis
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
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Chang J, Wu L, Tang L, Peng F, He J, Ni H, Liu J, Li S, Duan S, Chen X. The Effect and Mechanism of Fufang Banbianlian Injection in the Treatment of Mesangial Proliferative Glomerulonephritis. Comb Chem High Throughput Screen 2025; 28:278-290. [PMID: 38204248 DOI: 10.2174/0113862073272415231119133102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 01/12/2024]
Abstract
OBJECTIVE Mesangial proliferative glomerulonephritis (MsPGN) is an important cause of chronic kidney disease. Abnormal proliferation of mesangial cells and immune-inflammatory response are its important pathological manifestations. Currently, there is no ideal treatment for this disease. Fufang Banbianlian Injection (FBI) has anti-inflammatory, antioxidant, and immuneenhancing effects, and is mostly used for the treatment of bronchitis, pneumonia, and respiratory tract infections in children. METHODS A rat model of MsPGN was established and treated with FBI. The efficacy was tested through pathological experiments and urine protein quantification. Network pharmacology methods were used to predict the signaling pathways and key proteins that exert the efficacy of FBI, and were screened through molecular docking experiments. The active substances that work were verified through cell experiments. RESULTS The results confirmed that intervention with FBI can inhibit the proliferation of glomerular cells and reduce the infiltration of macrophages, thereby reducing the pathological damage of rats with mesangial proliferative nephritis; it has been found to have an obvious therapeutic effect. Molecular docking results have shown kaempferol (Kae), the main component of FBI, to have a good affinity for key targets. The results of in vitro verification experiments showed that FBI and its active ingredient Kae may play a therapeutic role by regulating the NF-κB signaling pathway in mesangial cells, inhibiting its activation and the secretion of proinflammatory cytokines. CONCLUSION Through network pharmacology, molecular docking, and experimental verification, it was confirmed that FBI and its active ingredient Kae can reduce the molecular mechanism of pathological damage of MsPGN by regulating the NF-κB signaling pathway and providing potential therapeutic drugs for the treatment of this disease.
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Affiliation(s)
- Jiakai Chang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Lingling Wu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Lifeng Tang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China
| | - Fei Peng
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Jiayi He
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Huiming Ni
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China
| | - Jiaona Liu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Shuang Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Shuwei Duan
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Xiangmei Chen
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou, 510006, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
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Yan Q, Du Y, Huang F, Zhang Q, Zhan M, Wu J, Yan J, Zhang P, Lin H, Han L, Huang X. Identification of mitochondria-related genes as diagnostic biomarkers for diabetic nephropathy and their correlation with immune infiltration: New insights from bioinformatics analysis. Int Immunopharmacol 2024; 142:113114. [PMID: 39265357 DOI: 10.1016/j.intimp.2024.113114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/20/2024] [Accepted: 09/05/2024] [Indexed: 09/14/2024]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a common and severe microvascular complication of diabetes. Mitochondrial dysfunction and immune inflammation are important factors in the pathogenesis of DN. However, the specific mechanisms and their intricate interactions in DN remain unclear. Besides, there are no effective specific predictive or diagnostic biomarkers for DN so far. Therefore, this study aims to elucidate the role of mitochondrial-related genes and their possibility as predictive or diagnostic biomarkers, as well as their crosstalk with immune infiltration in the progression of DN. METHODS Based on the GEO database and limma R package, the differentially expressed genes (DEGs) of DN were identified. Mitochondrial-related DEGs (MitoDEGs) were then obtained by intersecting these DEGs with mitochondria-related genes from the MitoCarta 3.0 database. Subsequently, the candidate hub genes were further screened by gene co-expression network analysis (WGCNA), and verified mRNA levels of these genes by real-time quantitative PCR (qRT-PCR) in high-glucose-treated human proximal tubular (HK-2) cells. The verified hub genes were utilized to construct a combined diagnostic model for DN, with its diagnostic efficacy assessed across the GSE30122 and GSE96804 datasets. Additionally, the immune infiltration pattern in DN was assessed with the CIBERSORT algorithm, and the Nephroseq v5 database was used to analyze the correlation between hub genes and clinical features of DN. RESULTS Seven mitochondria-related candidate hub genes were screened from 56 MitoDEGs. Subsequently, the expression levels of six of them, namely EFHD1, CASP3, AASS, MPC1, NT5DC2, and BCL2A1, exhibited significant inter-group differences in the HK-2 cell model. The diagnostic model based on the six genes demonstrated good diagnostic efficacy in both training and validation sets. Furthermore, correlation analysis indicated that EFHD1 and AASS, downregulated in DN, are positively correlated with eGFR and negatively with serum creatinine. Conversely, CASP3, NT5DC2, and BCL2A1, upregulated in DN, show opposite correlations. In addition, spearman analysis revealed that the six hub genes were significantly associated with the infiltration of immune cells, including M1 and M2 macrophages, mast cells, resting NK cells, gamma delta T cells, and follicular helper T cells. CONCLUSION This study elucidated the characteristics of mitochondria-related genes and their correlation with immune cell infiltration in DN, providing new insights for exploring the pathogenesis of DN and facilitating the identification of new potential biomarkers and therapeutic targets.
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Affiliation(s)
- Qiaofang Yan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China; Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yuanyuan Du
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China; Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Fei Huang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China; Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Qiaoxuan Zhang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China
| | - Min Zhan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China
| | - Junbiao Wu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China
| | - Jun Yan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China
| | - Pengwei Zhang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, 510120, China
| | - Haibiao Lin
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China
| | - Liqiao Han
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China.
| | - Xianzhang Huang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou 510120, China.
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Gali S, Kundu A, Sharma S, Ahn MY, Puia Z, Kumar V, Kim IS, Kwak JH, Palit P, Kim HS. Therapeutic potential of bark extracts from Macaranga denticulata on renal fibrosis in streptozotocin-induced diabetic rats. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2024; 87:911-933. [PMID: 39306745 DOI: 10.1080/15287394.2024.2394586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
Macaranga denticulata (MD) bark is commonly utilized in traditional medicine for diabetes prevention and treatment. The bark extract of MD is rich in prenyl or farnesyl flavonoids and stilbenes, which possess antioxidant properties. Although data suggest the potential therapeutic benefits of the use of MD in treating diabetic nephropathy (DN), the precise mechanisms underlying MD-initiated protective effects against DN are not well understood. This study aimed to assess the renoprotective properties of MD extract by examining renofibrosis inhibition, oxidative stress, and inflammation utilizing streptozotocin-induced DN male Sprague - Dawley rats. Diabetic rats were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After 6 days, these rats were orally administered MD extract (200 mg/kg/day) or metformin (200 mg/kg/day) for 14 days. The administration of MD extract significantly lowered blood glucose levels, restored body weight, and reduced urine levels of various biomarkers associated with kidney functions. Histopathological analysis revealed protective effects in both kidneys and pancreas. Further, MD extract significantly restored abnormalities in advanced glycation end products, oxidative stress biomarkers, and proinflammatory cytokine levels in STZ-treated rats. MD extract markedly reduced renal fibrosis biomarker levels, indicating recovery from renal injury, and reversed dysregulation of sirtuins and claudin-1 in the kidneys of rats with STZ-induced diabetes. In conclusion, data demonstrated the renoprotective role of MD extract, indicating plant extract's ability to suppress oxidative stress and regulate proinflammatory pathways during pathological changes in diabetic nephropathy.
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Affiliation(s)
- Sreevarsha Gali
- School of Pharmacy, Sungkyunkwan University, School of Pharmacy University, Suwon, Republic of Korea
| | - Amit Kundu
- School of Pharmacy, Sungkyunkwan University, School of Pharmacy University, Suwon, Republic of Korea
- Department of Pharmacology, GITAM School of Pharmacy, GITAM Deemed to be University, Visakhapatnam, India
| | - Swati Sharma
- School of Pharmacy, Sungkyunkwan University, School of Pharmacy University, Suwon, Republic of Korea
| | - Mee-Young Ahn
- Department of Biochemistry and Health Science, Changwon National University, Changwon-si, Republic of Korea
| | - Zothan Puia
- Department of Pharmacy, Regional Institute of Paramedical & Nursing Sciences, Aizawl, India
| | - Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Allahabad, India
| | - In Su Kim
- School of Pharmacy, Sungkyunkwan University, School of Pharmacy University, Suwon, Republic of Korea
| | - Jeong Hwan Kwak
- School of Pharmacy, Sungkyunkwan University, School of Pharmacy University, Suwon, Republic of Korea
| | - Partha Palit
- Department of Pharmaceutical Sciences, Drug Discovery Research Laboratory, Assam University, Silchar, India
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, School of Pharmacy University, Suwon, Republic of Korea
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Yáñez AJ, Jaramillo K, Silva P, Yáñez A M, Sandoval M, Carpio D, Aguilar M. Sodium tungstate (NaW) decreases inflammation and renal fibrosis in diabetic nephropathy. Am J Med Sci 2024; 368:518-531. [PMID: 38944202 DOI: 10.1016/j.amjms.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 05/30/2024] [Accepted: 06/06/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND Diabetic Nephropathy is one of the most severe complications of Diabetes Mellitus and the main cause of end-stage kidney disease worldwide. Despite the therapies available to control blood glucose and blood pressure, many patients continue to suffer from progressive kidney damage. Chronic hyperglycemia is the main driver of changes observed in diabetes; however, it was recently discovered that inflammation and oxidative stress contribute to the development and progression of kidney damage. Therefore, it is important to search for new pharmacological therapies that stop the progression of DN. Sodium tungstate (NaW) is an effective short and long-term antidiabetic agent in both type 1 and type 2 diabetes models. METHODS In this study, the effect of NaW on proinflammatory signalling pathways, proinflammatory proteins and fibrosis in the streptozotocin (STZ)-induced type 1 diabetic rat model was analysed using histological analysis, western blotting and immunohistochemistry. RESULTS NaW treatment in diabetic rats normalize parameters such as glycemia, glucosuria, albuminuria/creatinuria, glomerular damage, and tubulointerstitial damage. NaW decreased the proinflammatory signaling pathway NF-κB, inflammatory markers (ICAM-1, MCP-1 and OPN), profibrotic pathways (TGFβ1/Smad2/3), reduced epithelial-mesenchymal transition (α -SMA), and decreased renal fibrosis (type IV collagen). CONCLUSION NaW could be an effective drug therapy for treating human diabetic nephropathy.
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Affiliation(s)
- Alejandro J Yáñez
- Facultad de Ciencias, Universidad Austral de Chile, 5090000 Valdivia, Chile; Interdisciplinary Center for Aquaculture Research (INCAR), 4030000 Universidad de Concepción, Chile; Research and Development Department, Greenvolution SpA. Puerto Varas, Chile.
| | - Karen Jaramillo
- Facultad de Ciencias, Universidad Austral de Chile, 5090000 Valdivia, Chile
| | - Pamela Silva
- Facultad de Ciencias, Universidad Austral de Chile, 5090000 Valdivia, Chile
| | - Mariana Yáñez A
- Facultad de Medicina y Ciencias, Campus de la Patagonia, Universidad San Sebastian, 5480000 Puerto Montt, Chile
| | - Moises Sandoval
- Facultad de Ciencias, Universidad Austral de Chile, 5090000 Valdivia, Chile
| | - Daniel Carpio
- Facultad de Medicina, Universidad Austral de Chile, 5090000 Valdivia, Chile
| | - Marcelo Aguilar
- Facultad de Ciencias, Universidad Austral de Chile, 5090000 Valdivia, Chile.
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Sinha SK, Carpio MB, Nicholas SB. Fiery Connections: Macrophage-Mediated Inflammation, the Journey from Obesity to Type 2 Diabetes Mellitus and Diabetic Kidney Disease. Biomedicines 2024; 12:2209. [PMID: 39457523 PMCID: PMC11503991 DOI: 10.3390/biomedicines12102209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/12/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
The high prevalence of diabetes mellitus (DM) poses a significant public health challenge, with diabetic kidney disease (DKD) as one of its most serious consequences. It has become increasingly clear that type 2 DM (T2D) and the complications of DKD are not purely metabolic disorders. This review outlines emerging evidence related to the step-by-step contribution of macrophages to the development and progression of DKD in individuals who specifically develop T2D as a result of obesity. The macrophage is a prominent inflammatory cell that contributes to obesity, where adipocyte hypertrophy leads to macrophage recruitment and eventually to the expansion of adipose tissue. The recruited macrophages secrete proinflammatory cytokines, which cause systemic inflammation, glucose dysregulation, and insulin sensitivity, ultimately contributing to the development of T2D. Under such pathological changes, the kidney is susceptible to elevated glucose and thereby activates signaling pathways that ultimately drive monocyte recruitment. In particular, the early recruitment of proinflammatory macrophages in the diabetic kidney produces inflammatory cytokines/chemokines that contribute to inflammation and tissue damage associated with DKD pathology. Macrophage activation and recruitment are crucial inciting factors that also persist as DKD progresses. Thus, targeting macrophage activation and function could be a promising therapeutic approach, potentially offering significant benefits for managing DKD at all stages of progression.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Maria Beatriz Carpio
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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Bondi CD, Hartman HL, Rush BM, Tan RJ. Podocyte-Specific Deletion of MCP-1 Fails to Protect against Angiotensin II- or Adriamycin-Induced Glomerular Disease. Int J Mol Sci 2024; 25:4987. [PMID: 38732210 PMCID: PMC11084322 DOI: 10.3390/ijms25094987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.
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Affiliation(s)
- Corry D. Bondi
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 152671, USA; (H.L.H.); (B.M.R.); (R.J.T.)
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Fularski P, Czarnik W, Frankenstein H, Gąsior M, Młynarska E, Rysz J, Franczyk B. Unveiling Selected Influences on Chronic Kidney Disease Development and Progression. Cells 2024; 13:751. [PMID: 38727287 PMCID: PMC11083010 DOI: 10.3390/cells13090751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/14/2024] [Accepted: 04/16/2024] [Indexed: 05/13/2024] Open
Abstract
Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water-electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin-angiotensin-aldosterone system (RAAS) activity, transforming growth factor-β1 (TGF-β1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities.
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Affiliation(s)
- Piotr Fularski
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (M.G.)
| | - Witold Czarnik
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (M.G.)
| | - Hanna Frankenstein
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (M.G.)
| | - Magdalena Gąsior
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (M.G.)
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (M.G.)
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (M.G.)
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11
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Lin DW, Yang TM, Ho C, Shih YH, Lin CL, Hsu YC. Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease. Int J Mol Sci 2024; 25:4350. [PMID: 38673935 PMCID: PMC11050450 DOI: 10.3390/ijms25084350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition.
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Affiliation(s)
- Da-Wei Lin
- Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi City 60069, Taiwan;
| | - Tsung-Ming Yang
- Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan;
| | - Cheng Ho
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
| | - Ya-Hsueh Shih
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan
| | - Chun-Liang Lin
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan;
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 10507, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Yung-Chien Hsu
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi County 61363, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan
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12
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Jandeleit-Dahm KAM, Kankanamalage HR, Dai A, Meister J, Lopez-Trevino S, Cooper ME, Touyz RM, Kennedy CRJ, Jha JC. Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes. Antioxidants (Basel) 2024; 13:396. [PMID: 38671844 PMCID: PMC11047703 DOI: 10.3390/antiox13040396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.
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Affiliation(s)
- Karin A. M. Jandeleit-Dahm
- Department of Diabetes, School of Translational Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, VIC 3004, Australia; (K.A.M.J.-D.); (S.L.-T.); (M.E.C.)
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany;
| | - Haritha R. Kankanamalage
- Department of Diabetes, School of Translational Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, VIC 3004, Australia; (K.A.M.J.-D.); (S.L.-T.); (M.E.C.)
| | - Aozhi Dai
- Department of Diabetes, School of Translational Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, VIC 3004, Australia; (K.A.M.J.-D.); (S.L.-T.); (M.E.C.)
| | - Jaroslawna Meister
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany;
| | - Sara Lopez-Trevino
- Department of Diabetes, School of Translational Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, VIC 3004, Australia; (K.A.M.J.-D.); (S.L.-T.); (M.E.C.)
| | - Mark E. Cooper
- Department of Diabetes, School of Translational Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, VIC 3004, Australia; (K.A.M.J.-D.); (S.L.-T.); (M.E.C.)
| | - Rhian M. Touyz
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H3H 2R9, Canada;
| | - Christopher R. J. Kennedy
- Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada;
| | - Jay C. Jha
- Department of Diabetes, School of Translational Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, VIC 3004, Australia; (K.A.M.J.-D.); (S.L.-T.); (M.E.C.)
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13
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Youssef N, Noureldein MH, Riachi ME, Haddad A, Eid AA. Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression. Am J Physiol Renal Physiol 2024; 326:F301-F312. [PMID: 38153850 DOI: 10.1152/ajprenal.00266.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/29/2023] [Accepted: 12/16/2023] [Indexed: 12/30/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes affecting millions of people worldwide. Macrophages, a critical immune cell type, are central players in the development and progression of DKD. In this comprehensive review, we delve into the intricate role of macrophages in DKD, examining how they can become polarized into proinflammatory M1 or anti-inflammatory M2 phenotypes. We explore the signaling pathways involved in macrophage recruitment and polarization in the kidneys, including the key cytokines and transcription factors that promote M1 and M2 polarization. In addition, we discuss the latest clinical studies investigating macrophages in DKD and explore the potential of hypoglycemic drugs for modulating macrophage polarization. By gaining a deeper understanding of the mechanisms that regulate macrophage polarization in DKD, we may identify novel therapeutic targets for this debilitating complication of diabetes. This review provides valuable insights into the complex interplay between macrophages and DKD, shedding light on the latest developments in this important area of research. This review aims to enhance understanding of the role that macrophages play in the pathogenesis of DKD.
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Affiliation(s)
- Natalie Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed H Noureldein
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mansour E Riachi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Antony Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- American University of Beirut Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
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14
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Chen L, Lu S, Wu Z, Zhang E, Cai Q, Zhang X. Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets. MEDCOMM – FUTURE MEDICINE 2024; 3. [DOI: 10.1002/mef2.76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 02/18/2024] [Indexed: 01/02/2025]
Abstract
AbstractDiabetic nephropathy (DN) represents a prevalent chronic microvascular complication of diabetes mellitus (DM) and is a major cause of end‐stage renal disease. The anfractuous surrounding of DN pathogenesis and the intricate nature of this metabolic disorder often pose challenges in both the diagnosis and treatment of DN compared to other kidney diseases. Hyperglycaemia in DM predispose vulnerable renal cells into microenvironmental disequilibrium and thereby results in innate immunocytes infiltration including neutrophils, macrophages, myeloid‐derived suppressor cells, dendritic cells, and so forth. These immune cells play dual roles in kidney injury and closely correlated with the degree of proteinuria in DN patients. Additionally, innate immune signaling cascades, initiated by altered metabolic and hemodynamic in diabetic context, are crucial in instigating and perpetuating renal inflammation, which detrimentally contribute to DN pathogenesis. As such, anti‐inflammatory therapies, particularly those targeting innate immunity, hold renoprotective promise in DN. In this article, we reviewed the origin and feature of the above four prominent kidney innate immune cells, analyze their pathogenic role in DN, and discuss potential targeted‐therapeutic strategies, aiming to enhance the current understanding of renal innate immunity and hence help to discover promising therapeutic approaches for DN.
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Affiliation(s)
- Le‐Xin Chen
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Shu‐Ru Lu
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Zhi‐Hao Wu
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
| | - En‐Xin Zhang
- Shenzhen Bao'an Authentic TCM Therapy Hospital Shenzhen PR China
| | - Qing‐Qun Cai
- The First Affiliated Hospital Guangzhou University of Chinese Medicine Guangzhou PR China
| | - Xiao‐Jun Zhang
- School of Pharmaceutical Science Guangzhou University of Chinese Medicine Guangzhou PR China
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15
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Wang J, Chen W, Chen S, Yue G, Hu Y, Xu J. Landscape of infiltrating immune cells and related genes in diabetic kidney disease. Clin Exp Nephrol 2024; 28:181-191. [PMID: 37882850 DOI: 10.1007/s10157-023-02422-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/06/2023] [Indexed: 10/27/2023]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) is one of the prominent microvascular complications of diabetes and the leading cause of end-stage renal disease. Inflammation plays a crucial role in the development and progression of DKD. Currently, only a few studies depict the landscape of infiltrating immune cells and their potential regulatory network in DKD. To gain a better understanding of the role of immune cells in the renal microenvironment, we sought to reveal the profile of infiltrating immune cells and their potential regulatory network in DKD. METHODS We obtained the transcriptomes and the corresponding clinical data of 19 DKD and 25 control samples from the Gene Expression Omnibus and Nephroseq databases, respectively. Thereafter, we conducted an analysis on the infiltrating immune cells and identified immune-related differentially expressed genes through bioinformatics. Finally, correlation analyses among immune cells, immune genes, and clinical manifestations were performed, and differentially infiltrating immune cell subsets were verified through multiplex immunofluorescence staining. RESULTS We demonstrated the landscape of infiltrating immune cells in patients with DKD and identified the top five hub immune regulatory genes (C3, IL7R, TYROBP, BMP2, and CXCL6). Three of the core genes (C3, BMP2, and CXCL6) were significantly correlated with the estimated glomerular filtration rate. Through multiplex immunofluorescence staining, we verified that macrophage numbers were remarkably elevated, whereas Treg cells were remarkably reduced in diabetic kidney tissues. Th2 cells were scarce in the kidney tissue. CONCLUSION Collectively, our findings shed light on new, possible therapeutic strategies for DKD, from an immune microenvironment perspective.
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Affiliation(s)
- Jiao Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, No.17 Yongwaizheng St., Nanchang, Nanchang, 330006, Jiangxi, People's Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, People's Republic of China
- Jiangxi branch of national clinical research center for metabolic disease, Nanchang, 330006, People's Republic of China
| | - Wen Chen
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, No.17 Yongwaizheng St., Nanchang, Nanchang, 330006, Jiangxi, People's Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, People's Republic of China
- Jiangxi branch of national clinical research center for metabolic disease, Nanchang, 330006, People's Republic of China
| | - Shen Chen
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, No.17 Yongwaizheng St., Nanchang, Nanchang, 330006, Jiangxi, People's Republic of China
- Queen Mary School, Medical College, Nanchang University, Nanchang, 330006, People's Republic of China
| | - Guanru Yue
- Department of Medical Genetics and Cell biology, Medical College of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Ying Hu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, No.17 Yongwaizheng St., Nanchang, Nanchang, 330006, Jiangxi, People's Republic of China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, People's Republic of China
- Jiangxi branch of national clinical research center for metabolic disease, Nanchang, 330006, People's Republic of China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, No.17 Yongwaizheng St., Nanchang, Nanchang, 330006, Jiangxi, People's Republic of China.
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, People's Republic of China.
- Jiangxi branch of national clinical research center for metabolic disease, Nanchang, 330006, People's Republic of China.
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Swaminathan SM, Rao IR, Bhojaraja MV, Attur RP, Nagri SK, Rangaswamy D, Shenoy SV, Nagaraju SP. Role of novel biomarker monocyte chemo-attractant protein-1 in early diagnosis & predicting progression of diabetic kidney disease: A comprehensive review. J Natl Med Assoc 2024; 116:33-44. [PMID: 38195327 DOI: 10.1016/j.jnma.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 09/11/2023] [Accepted: 12/03/2023] [Indexed: 01/11/2024]
Abstract
Diabetic kidney disease (DKD) is the most devastating complication of diabetes mellitus. Identification of patients at the early stages of progression may reduce the disease burden. The limitation of conventional markers such as serum creatinine and proteinuria intensify the need for novel biomarkers. The traditional paradigm of DKD pathogenesis has expanded to the activation of the immune system and inflammatory pathways. Monocyte chemo-attractant protein-1 (MCP-1) is extensively studied, as a key inflammatory mediator that modulates the development of DKD. Recent evidence supports the diagnostic role of MCP-1 in patients with or without proteinuria in DKD, as well as a significant role in the early prediction and risk stratification of DKD. In this review, we will summarize and update present evidence for MCP-1 for diagnostic ability and predicting the progression of DKD.
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Affiliation(s)
- Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Mohan V Bhojaraja
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Ravindra Prabhu Attur
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Shivashankara Kaniyoor Nagri
- Department of Medicine, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba medical college, Manipal, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.
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Yang M, Zhang C. The role of innate immunity in diabetic nephropathy and their therapeutic consequences. J Pharm Anal 2024; 14:39-51. [PMID: 38352948 PMCID: PMC10859537 DOI: 10.1016/j.jpha.2023.09.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 07/12/2023] [Accepted: 09/05/2023] [Indexed: 02/16/2024] Open
Abstract
Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.
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Affiliation(s)
- Min Yang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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18
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Yang Q, Huo E, Cai Y, Zhang Z, Dong C, Asara JM, Shi H, Wei Q. Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis. Front Immunol 2023; 14:1259434. [PMID: 38035106 PMCID: PMC10687406 DOI: 10.3389/fimmu.2023.1259434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 10/27/2023] [Indexed: 12/02/2023] Open
Abstract
Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby's group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3 ΔMϕ ) and their wild type littermates (Pfkfb3 WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3 ΔMϕ mice compared to Pfkfb3 WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3 ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.
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Affiliation(s)
- Qiuhua Yang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Emily Huo
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Augusta Preparatory Day School, Martinez, GA, United States
| | - Yongfeng Cai
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Zhidan Zhang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Charles Dong
- Dental College of Georgia, Augusta University, Augusta, GA, United States
| | - John M. Asara
- Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Huidong Shi
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
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19
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Jiang S, Su H. Cellular crosstalk of mesangial cells and tubular epithelial cells in diabetic kidney disease. Cell Commun Signal 2023; 21:288. [PMID: 37845726 PMCID: PMC10577991 DOI: 10.1186/s12964-023-01323-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/17/2023] [Indexed: 10/18/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of end-stage renal disease and imposes a heavy global economic burden; however, little is known about its complicated pathophysiology. Investigating the cellular crosstalk involved in DKD is a promising avenue for gaining a better understanding of its pathogenesis. Nonetheless, the cellular crosstalk of podocytes and endothelial cells in DKD is better understood than that of mesangial cells (MCs) and renal tubular epithelial cells (TECs). As the significance of MCs and TECs in DKD pathophysiology has recently become more apparent, we reviewed the existing literature on the cellular crosstalk of MCs and TECs in the context of DKD to acquire a comprehensive understanding of their cellular communication. Insights into the complicated mechanisms underlying the pathophysiology of DKD would improve its early detection, care, and prognosis. Video Abstract.
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Affiliation(s)
- Shan Jiang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hua Su
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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20
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Li X, Liu J, Zeng M, Yang K, Zhang S, Liu Y, Yin X, Zhao C, Wang W, Xiao L. GBP2 promotes M1 macrophage polarization by activating the notch1 signaling pathway in diabetic nephropathy. Front Immunol 2023; 14:1127612. [PMID: 37622120 PMCID: PMC10445759 DOI: 10.3389/fimmu.2023.1127612] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
Background Diabetic nephropathy (DN) is one of the most common diabetic complications, which has become the primary cause of end-stage renal disease (ESRD) globally. Macrophage infiltration has been proven vital in the occurrence and development of DN. This study was designed to investigate the hub genes involved in macrophage-mediated inflammation of DN via bioinformatics analysis and experimental validation. Methods Gene microarray datasets were obtained from the Gene Expression Omnibus (GEO) public website. Integrating the CIBERSORT, weighted gene co-expression network analysis (WGCNA) and DEGs, we screened macrophage M1-associated key genes with the highest intramodular connectivity. Subsequently, the Least Absolute Shrinkage and Selection Operator (LASSO) regression was utilized to further mine hub genes. GSE104954 acted as an external validation to predict the expression levels and diagnostic performance of these hub genes. The Nephroseq online platform was employed to evaluate the clinical implications of these hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to elucidate the dominant biological functions and signal pathways. Finally, we conducted experiments to verify the role of GBP2 in M1 macrophage-mediated inflammatory response and the underlying mechanism of this role. Results Sixteen DEGs with the highest connectivity in M1 macrophages-associated module (paleturquoise module) were determined. Subsequently, we identified four hub genes through LASSO regression analysis, including CASP1, MS4A4A, CD53, and GBP2. Consistent with the training set, expression levels of these four hub genes manifested memorably elevated and the ROC curves indicated a good diagnostic accuracy with an area under the curve of greater than 0.8. Clinically, enhanced expression of these four hub genes predicted worse outcomes of DN patients. Given the known correlation between the first three hub genes and macrophage-mediated inflammation, experiments were performed to demonstrate the effect of GBP2, which proved that GBP2 contributed to M1 polarization of macrophages by activating the notch1 signaling pathway. Conclusion Our findings detected four hub genes, namely CASP1, MS4A4A, CD53, and GBP2, may involve in the progression of DN via pro-inflammatory M1 macrophage phenotype. GBP2 could be a promising prognostic biomarker and intervention target for DN by regulating M1 polarization.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Li Xiao
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, Changsha, China
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21
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Wang S, Zhang L, Jin Z, Wang Y, Zhang B, Zhao L. Visualizing temporal dynamics and research trends of macrophage-related diabetes studies between 2000 and 2022: a bibliometric analysis. Front Immunol 2023; 14:1194738. [PMID: 37564641 PMCID: PMC10410279 DOI: 10.3389/fimmu.2023.1194738] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/10/2023] [Indexed: 08/12/2023] Open
Abstract
Background Macrophages are considered an essential source of inflammatory cytokines, which play a pivotal role in the development of diabetes and its sequent complications. Therefore, a better understanding of the intersection between the development of diabetes and macrophage is of massive importance. Objectives In this study, we performed an informative bibliometric analysis to enlighten relevant research directions, provide valuable metrics for financing decisions, and help academics to gain a quick understanding of the current macrophage-related diabetes studies knowledge domain. Methods The Web of Science Core Collection database was used for literature retrieval and dataset export. Bibliometrix R-package was performed to conduct raw data screening, calculating, and visualizing. Results Between 2000 and 2022, the annual publication and citation trends steadily increased. Wu Yonggui was the scholar with the most published papers in this field. The institute with the highest number of published papers was the University of Michigan. The most robust academic collaboration was observed between China and the United States of America. Diabetologia was the journal that published the most relevant publications. The author's keywords with the highest occurrences were "inflammation", "diabetic nephropathy", and "obesity". In addition, "Macrophage polarization" was the current motor topic with potential research prospects. Conclusions These comprehensive and visualized bibliometric results summarized the significant findings in macrophage-related diabetes studies over the past 20 years. It would enlighten subsequent studies from a macro viewpoint and is also expected to strengthen investment policies in future macrophage-related diabetes studies.
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Affiliation(s)
- Sicheng Wang
- Institute of Metabolic Diseases, Guang’ Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lili Zhang
- Institute of Metabolic Diseases, Guang’ Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zishan Jin
- Institute of Metabolic Diseases, Guang’ Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Yayun Wang
- Institute of Metabolic Diseases, Guang’ Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, Changchun University of Chinese Medicine, Jilin, China
| | - Boxun Zhang
- Institute of Metabolic Diseases, Guang’ Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang’ Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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22
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Wang S, Qin S, Cai B, Zhan J, Chen Q. Promising therapeutic mechanism for Chinese herbal medicine in ameliorating renal fibrosis in diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:932649. [PMID: 37522131 PMCID: PMC10376707 DOI: 10.3389/fendo.2023.932649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/22/2023] [Indexed: 08/01/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most serious chronic microvascular abnormalities of diabetes mellitus and the major cause of uremia. Accumulating evidence has confirmed that fibrosis is a significant pathological feature that contributes to the development of chronic kidney disease in DN. However, the exact mechanism of renal fibrosis in DN is still unclear, which greatly hinders the treatment of DN. Chinese herbal medicine (CHM) has shown efficacy and safety in ameliorating inflammation and albuminuria in diabetic patients. In this review, we outline the underlying mechanisms of renal fibrosis in DN, including oxidative stress (OS) generation and OS-elicited ASK1-p38/JNK activation. Also, we briefly summarize the current status of CHM treating DN by improving renal fibrosis. The treatment of DN by inhibiting ASK1 activation to alleviate renal fibrosis in DN with CHM will promote the discovery of novel therapeutic targets for DN and provide a beneficial therapeutic method for DN.
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Affiliation(s)
- Shengju Wang
- Department of Nephrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shuai Qin
- Department of Nephrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Baochao Cai
- Diabetes Department, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, Zhejiang, China
| | - Jihong Zhan
- Department of Nephrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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23
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Jin S, Song Y, Zhou L, Jiang W, Qin L, Wang Y, Yu R, Liu Y, Diao Y, Zhang F, Liu K, Li P, Hu H, Jiang B, Tang W, Yi F, Gong Y, Liu G, Sun G. Depletion of CUL4B in macrophages ameliorates diabetic kidney disease via miR-194-5p/ITGA9 axis. Cell Rep 2023; 42:112550. [PMID: 37224018 DOI: 10.1016/j.celrep.2023.112550] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 02/26/2023] [Accepted: 05/08/2023] [Indexed: 05/26/2023] Open
Abstract
Diabetic kidney disease (DKD) is the most prevalent chronic kidney disease. Macrophage infiltration in the kidney is critical for the progression of DKD. However, the underlying mechanism is far from clear. Cullin 4B (CUL4B) is the scaffold protein in CUL4B-RING E3 ligase complexes. Previous studies have shown that depletion of CUL4B in macrophages aggravates lipopolysaccharide-induced peritonitis and septic shock. In this study, using two mouse models for DKD, we demonstrate that myeloid deficiency of CUL4B alleviates diabetes-induced renal injury and fibrosis. In vivo and in vitro analyses reveal that loss of CUL4B suppresses migration, adhesion, and renal infiltration of macrophages. Mechanistically, we show that high glucose upregulates CUL4B in macrophages. CUL4B represses expression of miR-194-5p, which leads to elevated integrin α9 (ITGA9), promoting migration and adhesion. Our study suggests the CUL4B/miR-194-5p/ITGA9 axis as an important regulator for macrophage infiltration in diabetic kidneys.
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Affiliation(s)
- Shiqi Jin
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yu Song
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Li Zhou
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Wei Jiang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Liping Qin
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yufeng Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Ruiqi Yu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yuting Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yujie Diao
- Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Fan Zhang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Kaixuan Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Peishan Li
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China
| | - Huili Hu
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Systems Biomedicine and Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Baichun Jiang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Wei Tang
- Department of Pathogenic Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Fan Yi
- Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yaoqin Gong
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Guangyi Liu
- Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Gongping Sun
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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Qiu Y, Tang J, Zhao Q, Jiang Y, Liu YN, Liu WJ. From Diabetic Nephropathy to End-Stage Renal Disease: The Effect of Chemokines on the Immune System. J Diabetes Res 2023; 2023:3931043. [PMID: 37287620 PMCID: PMC10243947 DOI: 10.1155/2023/3931043] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 06/09/2023] Open
Abstract
Background Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), and there is growing evidence to support the role of immunity in the progression of DN to ESRD. Chemokines and chemokine receptors (CCRs) can recruit immune cells to sites of inflammation or injury. Currently, no studies have reported the effect of CCRs on the immune environment during the progression of DN to ESRD. Methods Differentially expressed genes (DEGs) from the GEO database were identified in DN patients versus ESRD patients. GO and KEGG enrichment analyses were performed using DEGs. A protein-protein interaction (PPI) network was constructed to identify hub CCRs. Differentially expressed immune cells were screened by immune infiltration analysis, and the correlation between immune cells and hub CCRs was also calculated. Result In this study, a total of 181 DEGs were identified. Enrichment analysis showed that chemokines, cytokines, and inflammation-related pathways were significantly enriched. Combining the PPI network and CCRs, four hub CCRs (CXCL2, CXCL8, CXCL10, and CCL20) were identified. These hub CCRs showed an upregulation trend in DN patients and a downregulation trend in ESRD patients. Immune infiltration analysis identified a variety of immune cells that underwent significant changes during disease progression. Among them, CD56bright natural killer cell, effector memory CD8 T cell, memory B cell, monocyte, regulatory T cell, and T follicular helper cell were significantly associated with all hub CCR correlation. Conclusion The effect of CCRs on the immune environment may contribute to the progression of DN to ESRD.
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Affiliation(s)
- Yuheng Qiu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Qihan Zhao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yuhua Jiang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yu Ning Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Wei Jing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
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25
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Bao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, et alBao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, Wang S, Wang X, Wang X, Wang YJ, Wang Y, Wong CCL, Xiang AP, Xiao Y, Xie Z, Xu D, Ye J, Yue R, Zhang C, Zhang H, Zhang L, Zhang W, Zhang Y, Zhang YW, Zhang Z, Zhao T, Zhao Y, Zhu D, Zou W, Pei G, Liu GH. Biomarkers of aging. SCIENCE CHINA. LIFE SCIENCES 2023; 66:893-1066. [PMID: 37076725 PMCID: PMC10115486 DOI: 10.1007/s11427-023-2305-0] [Show More Authors] [Citation(s) in RCA: 163] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/27/2023] [Indexed: 04/21/2023]
Abstract
Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.
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Affiliation(s)
- Hainan Bao
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Jiani Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Mengting Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Chen
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Chen
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Third Military Medical University, Chongqing, 400042, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yutian Chen
- The Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhiyang Chen
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Jagadish K Chhetri
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Yingjie Ding
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Junlin Feng
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jun Guo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Mengmeng Guo
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Chuting He
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Yujuan Jia
- Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, 030001, China
| | - Haiping Jiang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Jing
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Dingfeng Li
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China
| | - Jiaming Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingyi Li
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Qinhao Liang
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China
| | - Rui Liang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China
| | - Feng Liu
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zuojun Liu
- School of Life Sciences, Hainan University, Haikou, 570228, China
| | - Oscar Junhong Luo
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jianwei Lv
- School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jingyi Ma
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kehang Mao
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China
| | - Jiawei Nie
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinhua Qiao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xinpei Sun
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China
| | - Xiaoqiang Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Jianfang Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Qiaoran Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Siyuan Wang
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Xuan Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Yaning Wang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuhan Wang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Rimo Wu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China
| | - Kai Xia
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Fu-Hui Xiao
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Lingyan Xu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yingying Xu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Haoteng Yan
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Liang Yang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China
| | - Ruici Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuanxin Yang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
| | - Yilin Ying
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China
| | - Le Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiwei Zhang
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China
| | - Wenwan Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xing Zhang
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuo Zhang
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Min Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Rui Zhou
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Qingchen Zhu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhengmao Zhu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.
| | - Zhongwei Cao
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Piu Chan
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Chang Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, Guangzhou, 510000, China.
| | - Hou-Zao Chen
- Department of Biochemistryand Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
| | - Jun Chen
- Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University, Beijing, 100191, China.
| | - Weimin Ci
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
| | - Bi-Sen Ding
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Feng Gao
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China.
| | - Kai Huang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
| | - Qing-Peng Kong
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
| | - Xin Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Baohua Liu
- School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China.
| | - Feng Liu
- Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South Unversity, Changsha, 410011, China.
| | - Lin Liu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China.
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Institute of Translational Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, 300000, China.
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
| | - Qiang Liu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
| | - Qiang Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Tianjin Institute of Immunology, Tianjin Medical University, Tianjin, 300070, China.
| | - Xingguo Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China.
| | - Yong Liu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China.
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China.
| | - Shuai Ma
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Jing Nie
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Yaojin Peng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jie Ren
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Ruibao Ren
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Center for Aging and Cancer, Hainan Medical University, Haikou, 571199, China.
| | - Moshi Song
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Zhou Songyang
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China.
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Yi Eve Sun
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA.
| | - Mei Tian
- Human Phenome Institute, Fudan University, Shanghai, 201203, China.
| | - Shusen Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China.
| | - Si Wang
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| | - Xia Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
| | - Xiaoning Wang
- Institute of Geriatrics, The second Medical Center, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Yan-Jiang Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
| | - Yunfang Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China.
| | - Catherine C L Wong
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Zhengwei Xie
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China.
- Beijing & Qingdao Langu Pharmaceutical R&D Platform, Beijing Gigaceuticals Tech. Co. Ltd., Beijing, 100101, China.
| | - Daichao Xu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
| | - Jing Ye
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China.
| | - Rui Yue
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Cuntai Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China.
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Hongbo Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Liang Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yong Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Yun-Wu Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, China.
| | - Zhuohua Zhang
- Key Laboratory of Molecular Precision Medicine of Hunan Province and Center for Medical Genetics, Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410078, China.
- Department of Neurosciences, Hengyang Medical School, University of South China, Hengyang, 421001, China.
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Yuzheng Zhao
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Dahai Zhu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Gang Pei
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200070, China.
| | - Guang-Hui Liu
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
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Swaminathan SM, Rao IR, Shenoy SV, Prabhu AR, Mohan PB, Rangaswamy D, Bhojaraja MV, Nagri SK, Nagaraju SP. Novel biomarkers for prognosticating diabetic kidney disease progression. Int Urol Nephrol 2023; 55:913-928. [PMID: 36271990 PMCID: PMC10030535 DOI: 10.1007/s11255-022-03354-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 08/21/2022] [Indexed: 10/24/2022]
Abstract
The global burden of diabetic kidney disease (DKD) is escalating, and it remains as a predominant cause of the end-stage renal disease (ESRD). DKD is associated with increased cardiovascular disease and morbidity in all types of diabetes. Prediction of progression with albuminuria and eGFR is challenging in DKD, especially in non-proteinuric DKD patients. The pathogenesis of DKD is multifactorial characterized by injury to all components of the nephron, whereas albuminuria is an indicator of only glomerular injury. The limits in the diagnostic and prognostic value of urine albumin demonstrate the need for alternative and clinically significant early biomarkers, allowing more targeted and effective diabetic treatment, to reduce the burden of DKD and ESRD. Identification of biomarkers, based on multifactorial pathogenesis of DKD can be the crucial paradigm in the treatment algorithm of DKD patients. This review focuses on the potential biomarkers linked to DKD pathogenesis, particularly with the hope of broadening the diagnostic window to identify patients with different stages of DKD progression.
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Affiliation(s)
- Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Attur Ravindra Prabhu
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Mohan V Bhojaraja
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Shivashankara Kaniyoor Nagri
- Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India.
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27
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Gui Y, Palanza Z, Fu H, Zhou D. Acute kidney injury in diabetes mellitus: Epidemiology, diagnostic, and therapeutic concepts. FASEB J 2023; 37:e22884. [PMID: 36943403 PMCID: PMC10602403 DOI: 10.1096/fj.202201340rr] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 02/16/2023] [Accepted: 03/08/2023] [Indexed: 03/23/2023]
Abstract
Acute kidney injury (AKI) and diabetes mellitus (DM) are public health problems that cause a high socioeconomic burden worldwide. In recent years, the landscape of AKI etiology has shifted: Emerging evidence has demonstrated that DM is an independent risk factor for the onset of AKI, while an alternative perspective considers AKI as a bona fide complication of DM. Therefore, it is necessary to systematically characterize the features of AKI in DM. In this review, we summarized the epidemiology of AKI in DM. While focusing on circulation- and tissue-specific microenvironment changes after DM, we described the active cellular and molecular mechanisms of increased kidney susceptibility to AKI under DM stress. We also reviewed the current diagnostic and therapeutic strategies for AKI in DM recommended in the clinic. Updated recognition of the epidemiology, pathophysiology, diagnosis, and medications of AKI in DM is believed to reveal a path to mitigate the frequency of AKI and DM comorbidity that will ultimately improve the quality of life in DM patients.
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Affiliation(s)
- Yuan Gui
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
| | - Zachary Palanza
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
| | - Haiyan Fu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | - Dong Zhou
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
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28
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Good PI, Li L, Hurst HA, Serrano Herrera I, Xu K, Rao M, Bateman DA, Al-Awqati Q, D’Agati VD, Costantini F, Lin F. Low nephron endowment increases susceptibility to renal stress and chronic kidney disease. JCI Insight 2023; 8:e161316. [PMID: 36626229 PMCID: PMC9977438 DOI: 10.1172/jci.insight.161316] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023] Open
Abstract
Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated potentially novel mouse models with a 30%-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy, followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared with controls with normal nephron number. Mice with low nephron number had reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.
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Affiliation(s)
| | - Ling Li
- Department of Pediatrics and
| | | | | | - Katherine Xu
- Department of Internal Medicine, Columbia University Vagelos College of Physicians and Surgeons New York, New York, USA
| | - Meenakshi Rao
- Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston Massachusetts, USA
| | | | - Qais Al-Awqati
- Department of Internal Medicine, Columbia University Vagelos College of Physicians and Surgeons New York, New York, USA
| | - Vivette D. D’Agati
- Department of Pathology and Cellular Biology at Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Frank Costantini
- Department of Genetics and Development at Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
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29
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Jiang Y, Cai C, Zhang P, Luo Y, Guo J, Li J, Rong R, Zhang Y, Zhu T. Transcriptional profile changes after treatment of ischemia reperfusion injury-induced kidney fibrosis with 18β-glycyrrhetinic acid. Ren Fail 2022; 44:660-671. [PMID: 35699239 PMCID: PMC9225714 DOI: 10.1080/0886022x.2022.2061998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Introduction Chronic kidney disease (CKD) is characterized by renal fibrosis without effective therapy. 18β-Glycyrrhetinic acid (GA) is reported to have detoxification and anti-inflammatory functions and promotes tissue repair. However, the role of GA in CKD remains unclear. In this study, we investigated whether GA has a potential therapeutic effect in kidney fibrosis. Methods A renal fibrosis mouse model was established by ischemia/reperfusion (I/R) injury via clamping unilateral left renal pedicle for 45 min; then, the mice were treated with vehicle or GA. Kidney tissues and blood samples were extracted 14 days after reperfusion and renal function, histopathological staining, quantitative PCR, and western blotting were performed. RNA-seq was performed to explore the changes in the transcriptional profile after GA treatment. Results Renal function, pathological and molecular analysis displayed that fibrosis was successfully induced in the I/R model. In the GA treatment group, the severity of fibrosis gradually reduced with the best effect seen at a concentration of 25 mg kg −1. A total of 970 differentially expressed genes were identified. Pathway enrichment showed that reduced activation and migration of inflammatory cells and decreased chemokine interaction in significant pathways. Protein–protein interaction networks were constructed and 15 hub genes were selected by degree rank, including chemokines, such as C3, Ccl6, Ccr2, Ptafr, Timp1, and Pf4. Conclusions GA may alleviate renal fibrosis by inhibiting the inflammatory response. GA is a promising therapy that may perhaps be used in treating renal fibrosis and CKD.
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Affiliation(s)
- Yamei Jiang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
| | - Chengzhe Cai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Pingbao Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
| | - Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
| | - Jingjing Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
| | - Jiawei Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
| | - Yi Zhang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China.,Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, P. R. China
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30
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Mitrofanova A, Fontanella A, Tolerico M, Mallela S, Molina David J, Zuo Y, Boulina M, Kim JJ, Santos J, Ge M, Sloan A, Issa W, Gurumani M, Pressly J, Ito M, Kretzler M, Eddy S, Nelson R, Merscher S, Burke G, Fornoni A. Activation of Stimulator of IFN Genes (STING) Causes Proteinuria and Contributes to Glomerular Diseases. J Am Soc Nephrol 2022; 33:2153-2173. [PMID: 36198430 PMCID: PMC9731637 DOI: 10.1681/asn.2021101286] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 09/06/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The signaling molecule stimulator of IFN genes (STING) was identified as a crucial regulator of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-STING pathway, and this signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI. However, the role of STING in causing CKD, including diabetic kidney disease (DKD) and Alport syndrome, is unknown. METHODS To investigate whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome, immortalized human and murine podocytes were differentiated for 14 days and treated with a STING-specific agonist. We used diabetic db/db mice, mice with experimental Alport syndrome, C57BL/6 mice, and STING knockout mice to assess the role of the STING signaling pathway in kidney failure. RESULTS In vitro, murine and human podocytes express all of the components of the cGAS-STING pathway. In vivo, activation of STING renders C57BL/6 mice susceptible to albuminuria and podocyte loss. STING is activated at baseline in mice with experimental DKD and Alport syndrome. STING activation occurs in the glomerular but not the tubulointerstitial compartment in association with autophagic podocyte death in Alport syndrome mice and with apoptotic podocyte death in DKD mouse models. Genetic or pharmacologic inhibition of STING protects from progression of kidney disease in mice with DKD and Alport syndrome and increases lifespan in Alport syndrome mice. CONCLUSION The activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Targeting STING may offer a therapeutic option to treat glomerular diseases of metabolic and nonmetabolic origin or prevent their development, progression, or both.
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Affiliation(s)
- Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida
| | - Antonio Fontanella
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Matthew Tolerico
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Shamroop Mallela
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Judith Molina David
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Yiqin Zuo
- Department of Pathology, University of Miami Medical Group, Miller School of Medicine, Miami, Florida
| | - Marcia Boulina
- Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, Florida
| | - Jin-Ju Kim
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Javier Santos
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Mengyuan Ge
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Alexis Sloan
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Wadih Issa
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Margaret Gurumani
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Jeffrey Pressly
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Marie Ito
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Matthias Kretzler
- Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Sean Eddy
- Division of Nephrology, Departments of Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Robert Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - George Burke
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida
- Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, Florida
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida
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Identification of Ribonuclease 6 as an immunoinflammatory key gene associated with the glomerular injury in diabetic nephropathy. Sci Rep 2022; 12:19709. [PMID: 36385487 PMCID: PMC9668917 DOI: 10.1038/s41598-022-24289-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetic nephropathy is one of the major causes of end-stage renal disease, and the pathogenesis of the disease has not been elucidated. While the immunoinflammatory response plays an essential role in the progression of diabetic nephropathy. Glomerular expression dataset in diabetic nephropathy was obtained from the GEO database. Differentially expressed genes were identified and functional enrichment analysis was performed to find genes associated with immunity and inflammation from them. The hub genes of immunoinflammatory were identified using MCODE after establishing the PPI network and gene expression was verified with diabetic nephropathy model rats. Xcell was used to assign immune cells to diabetic nephropathy glomerular samples to detect significant changes in immune cells and to analyze correlations with the hub gene. We found 120 DEGs associated with immunity and inflammation, Ribonuclease 6 was the Hub gene with the highest MCODE score. Xcell analysis revealed significant changes of immune cells in DN glomeruli, including upregulated Activated DCs, Conventional DCs, CD4+ Tem, Epithelial cells, Macrophages, Macrophages M1, and Memory B-cells. RNase6 expression showed the highest positive correlation with Macrophages M1, Activated DCs, and Conventional DCs. We verified through the Nephroseq v5 database that RNase6 expression was elevated in DN glomeruli and negatively correlated with glomerular filtration rate. Animal studies revealed that the kidney of DN model rats showed increased RNase6 expression together with inflammatory factor TNF-alpha and chemokine MCP-1. Our study identified RNase6 as a diagnostic and prognostic biomarker for diabetic nephropathy and found that it may play an essential role in the immunoinflammatory damage to the glomerulus.
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Li HD, You YK, Shao BY, Wu WF, Wang YF, Guo JB, Meng XM, Chen H. Roles and crosstalks of macrophages in diabetic nephropathy. Front Immunol 2022; 13:1015142. [PMID: 36405700 PMCID: PMC9666695 DOI: 10.3389/fimmu.2022.1015142] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/20/2022] [Indexed: 11/05/2022] Open
Abstract
Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.
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Affiliation(s)
- Hai-Di Li
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yong-Ke You
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China
| | - Bao-Yi Shao
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wei-Feng Wu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yi-Fan Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jian-Bo Guo
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- *Correspondence: Haiyong Chen, ; Xiao-Ming Meng,
| | - Haiyong Chen
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Haiyong Chen, ; Xiao-Ming Meng,
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Potential Roles of Anti-Inflammatory Plant-Derived Bioactive Compounds Targeting Inflammation in Microvascular Complications of Diabetes. Molecules 2022; 27:molecules27217352. [PMID: 36364178 PMCID: PMC9657994 DOI: 10.3390/molecules27217352] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders, the characteristics of which include chronic hyperglycemia owing to defects in insulin function, insulin secretion, or both. Inflammation plays a crucial role in DM pathogenesis and innate immunity in the development of microvascular complications of diabetes. In addition, hyperglycemia and DM mediate a proinflammatory microenvironment that can result in various microvascular complications, including diabetic nephropathy (DNP), diabetic neuropathy (DN), and diabetic retinopathy (DR). DNP is a major cause of end-stage renal disease. DNP can lead to albuminuria, decreased filtration, mesangium expansion, thickening of the basement membrane, and eventually renal failure. Furthermore, inflammatory cells can accumulate in the interstitium and glomeruli to deteriorate DNP. DN is another most prevalent microvascular complication of DM and the main cause of high mortality, disability, and a poor quality of life. DNs have a wide range of clinical manifestations because of the types of fiber dysfunctions and complex structures of the peripheral nervous system. DR is also a microvascular and multifactorial disease, as well as a major cause of visual impairment globally. Pathogenesis of DR is yet to be fully revealed, however, numerous studies have already confirmed the role of inflammation in the onset and advancement of DR. Despite evidence, and better knowledge regarding the pathogenesis of these microvascular complications of diabetes, there is still a deficiency of effective therapies. Bioactive compounds are mainly derived from plants, and these molecules have promising therapeutic potential. In this review, evidence and molecular mechanisms regarding the role of inflammation in various microvascular complications of diabetes including DNP, DN, and DR, have been summarized. The therapeutic potential of several bioactive compounds derived from plants in the treatment of these microvascular complications of diabetes has also been discussed.
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Cao H, Rao X, Jia J, Yan T, Li D. Exploring the pathogenesis of diabetic kidney disease by microarray data analysis. Front Pharmacol 2022; 13:932205. [PMID: 36059966 PMCID: PMC9428563 DOI: 10.3389/fphar.2022.932205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, and the leading contributor of end-stage renal disease. Hence, insights into the molecular pathogenesis of DKD are urgently needed. The purpose of this article is to reveal the molecular mechanisms underlying the pathogenesis of DKD. The microarray datasets of GSE30528 and GSE30529 were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify the common differentially expressed genes (DEGs) between the glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to analyze the function and pathways of the common DEGs. After constructing the protein–protein interaction (PPI) network and subnetwork analysis, three types of analyses were performed, namely, identification of hub genes, analysis of the coexpressed network, and exploration of transcription factors (TFs). Totally, 348 and 463 DEGs were identified in GDKD and TDKD, respectively. Then, 66 common DEGs (63 upregulated DEGs and three downregulated DEGs) were obtained in DKD patients. GO and KEGG pathway analyses revealed the importance of inflammation response, immune-related pathways, and extracellular matrix-related pathways, especially chemokines and cytokines, in DKD. Fifteen hub genes from the 66 common DEGs, namely, IL10RA, IRF8, LY86, C1QA, C1QB, CD53, CD1C, CTSS, CCR2, CD163, CCL5, CD48, RNASE6, CD52, and CD2 were identified. In summary, through the microarray data analysis, the common functions and hub genes greatly contribute to the elucidation of the molecular pathogenesis associated with DKD.
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Affiliation(s)
- Haiyan Cao
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaosheng Rao
- Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Junya Jia
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tiekun Yan
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
| | - Dong Li
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
- *Correspondence: Dong Li,
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Estupiñán-Moreno E, Ortiz-Fernández L, Li T, Hernández-Rodríguez J, Ciudad L, Andrés-León E, Terron-Camero LC, Prieto-González S, Espígol-Frigolé G, Cid MC, Márquez A, Ballestar E, Martín J. Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids. Ann Rheum Dis 2022; 81:1290-1300. [PMID: 35705375 PMCID: PMC9380516 DOI: 10.1136/annrheumdis-2022-222156] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/17/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. METHODS We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. RESULTS We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2. CONCLUSION Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.
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Affiliation(s)
- Elkyn Estupiñán-Moreno
- Institute of Parasitology and Biomedicine López-Neyra (IPBLN), Spanish National Research Council (CSIC), Granada, Spain
| | - Lourdes Ortiz-Fernández
- Institute of Parasitology and Biomedicine López-Neyra (IPBLN), Spanish National Research Council (CSIC), Granada, Spain
| | - Tianlu Li
- Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain
| | - Jose Hernández-Rodríguez
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Ciudad
- Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain
| | - Eduardo Andrés-León
- Institute of Parasitology and Biomedicine López-Neyra (IPBLN), Spanish National Research Council (CSIC), Granada, Spain
| | - Laura Carmen Terron-Camero
- Institute of Parasitology and Biomedicine López-Neyra (IPBLN), Spanish National Research Council (CSIC), Granada, Spain
| | - Sergio Prieto-González
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Georgina Espígol-Frigolé
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Maria Cinta Cid
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ana Márquez
- Institute of Parasitology and Biomedicine López-Neyra (IPBLN), Spanish National Research Council (CSIC), Granada, Spain
- Systemic Autoimmune Diseases Unit, Hospital Clinico San Cecilio, Instituto de Investigación Biosanitaria de Granada ibs.GRANADA, Granada, Spain
| | - Esteban Ballestar
- Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain
| | - Javier Martín
- Institute of Parasitology and Biomedicine López-Neyra (IPBLN), Spanish National Research Council (CSIC), Granada, Spain
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Rico-Fontalvo J, Aroca G, Cabrales J, Daza-Arnedo R, Yánez-Rodríguez T, Martínez-Ávila MC, Uparella-Gulfo I, Raad-Sarabia M. Molecular Mechanisms of Diabetic Kidney Disease. Int J Mol Sci 2022; 23:ijms23158668. [PMID: 35955802 PMCID: PMC9369345 DOI: 10.3390/ijms23158668] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 12/18/2022] Open
Abstract
The inflammatory component of diabetic kidney disease has become of great interest in recent years, with genetic and epigenetic variants playing a fundamental role in the initiation and progression of the disease. Cells of the innate immune system play a major role in the pathogenesis of diabetic kidney disease, with a lesser contribution from the adaptive immune cells. Other components such as the complement system also play a role, as well as specific cytokines and chemokines. The inflammatory component of diabetic kidney disease is of great interest and is an active research field, with the hope to find potential innovative therapeutic targets.
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Affiliation(s)
- Jorge Rico-Fontalvo
- Colombian Nephrology Association, Bogotá 110221, Colombia
- Management of Technologies and Innovation, Department of Engineering, Universidad Simón Bolivar, Cl. 58 #55-132, Barranquilla 080002, Colombia
| | - Gustavo Aroca
- Colombian Nephrology Association, Bogotá 110221, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla 080002, Colombia
| | - Jose Cabrales
- Nephrology Fellow, Stanford University School of Medicine, Palo Alto, CA 94305, USA
- Correspondence:
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Aboolian A, Urner S, Roden M, Jha JC, Jandeleit-Dahm K. Diabetic Kidney Disease: From Pathogenesis to Novel Treatment Possibilities. Handb Exp Pharmacol 2022; 274:269-307. [PMID: 35318511 DOI: 10.1007/164_2021_576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
One of the microvascular complications of diabetes is diabetic kidney disease (DKD), often leading to end stage renal disease (ESRD) in which patients require costly dialysis or transplantation. The silent onset and irreversible progression of DKD are characterized by a steady decline of the estimated glomerular filtration rate, with or without concomitant albuminuria. The diabetic milieu allows the complex pathophysiology of DKD to enter a vicious cycle by inducing the synthesis of excessive amounts of reactive oxygen species (ROS) causing oxidative stress, inflammation, and fibrosis. As no cure is available, intensive research is required to develop novel treatments possibilities. This chapter provides an overview of the important pathomechanisms identified in diabetic kidney disease, the currently established therapies, as well as recently developed novel therapeutic strategies in DKD.
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Affiliation(s)
- Ara Aboolian
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sofia Urner
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Centre for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Jay Chandra Jha
- Department of Diabetes, Monash University, Melbourne, VIC, Australia
| | - Karin Jandeleit-Dahm
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
- Department of Diabetes, Monash University, Melbourne, VIC, Australia.
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Magkrioti C, Antonopoulou G, Fanidis D, Pliaka V, Sakellaropoulos T, Alexopoulos LG, Ullmer C, Aidinis V. Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells. Int J Mol Sci 2022; 23:ijms23137452. [PMID: 35806457 PMCID: PMC9267536 DOI: 10.3390/ijms23137452] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 06/28/2022] [Accepted: 07/02/2022] [Indexed: 02/01/2023] Open
Abstract
Chronic kidney disease (CKD) refers to a spectrum of diseases defined by renal fibrosis, permanent alterations in kidney structure, and low glomerular-filtration rate. Prolonged epithelial-tubular damage involves a series of changes that eventually lead to CKD, highlighting the importance of tubular epithelial cells in this process. Lysophosphatidic acid (LPA) is a bioactive lipid that signals mainly through its six cognate LPA receptors and is implicated in several chronic inflammatory pathological conditions. In this report, we have stimulated human proximal tubular epithelial cells (HKC-8) with LPA and 175 other possibly pathological stimuli, and simultaneously detected the levels of 27 intracellular phosphoproteins and 32 extracellular secreted molecules with multiplex ELISA. This quantification revealed a large amount of information concerning the signaling and the physiology of HKC-8 cells that can be extrapolated to other proximal tubular epithelial cells. LPA responses clustered with pro-inflammatory stimuli such as TNF and IL-1, promoting the phosphorylation of important inflammatory signaling hubs, including CREB1, ERK1, JUN, IκΒα, and MEK1, as well as the secretion of inflammatory factors of clinical relevance, including CCL2, CCL3, CXCL10, ICAM1, IL-6, and IL-8, most of them shown for the first time in proximal tubular epithelial cells. The identified LPA-induced signal-transduction pathways, which were pharmacologically validated, and the secretion of the inflammatory factors offer novel insights into the possible role of LPA in CKD pathogenesis.
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Affiliation(s)
- Christiana Magkrioti
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece; (C.M.); (G.A.); (D.F.)
| | - Georgia Antonopoulou
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece; (C.M.); (G.A.); (D.F.)
| | - Dionysios Fanidis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece; (C.M.); (G.A.); (D.F.)
| | - Vaia Pliaka
- ProtATonce Ltd., 15343 Athens, Greece; (V.P.); (T.S.); (L.G.A.)
| | | | - Leonidas G. Alexopoulos
- ProtATonce Ltd., 15343 Athens, Greece; (V.P.); (T.S.); (L.G.A.)
- School of Mechanical Engineering, National Technical University of Athens, 15780 Zografou, Greece
| | - Christoph Ullmer
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland;
| | - Vassilis Aidinis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece; (C.M.); (G.A.); (D.F.)
- Correspondence:
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Shahzad K, Fatima S, Khawaja H, Elwakiel A, Gadi I, Ambreen S, Zimmermann S, Mertens PR, Biemann R, Isermann B. Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease. Kidney Int 2022; 102:766-779. [PMID: 35779608 DOI: 10.1016/j.kint.2022.06.010] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 05/20/2022] [Accepted: 06/10/2022] [Indexed: 12/15/2022]
Abstract
Efficient therapies for diabetic kidney disease (DKD), now the leading cause of kidney failure, are lacking. One hallmark of DKD is sterile inflammation (inflammation in absence of microorganisms), but the underlying molecular mechanisms remain poorly understood. The NLRP3 inflammasome (innate immune system receptors and sensors regulating activation of caspase-1) is a mechanism of sterile inflammation known to be activated by metabolic stimuli and reactive metabolites associated with DKD, including inflammasome activation in podocytes. However, whether NLRP3 inflammasome activation in podocytes contributes to sterile inflammation and glomerular damage in DKD remains unknown. Here, we found that kidney damage, as reflected by increased albuminuria, glomerular mesangial expansion and glomerular basement membrane thickness was aggravated in hyperglycemic mice with podocyte-specific expression of an Nlrp3 gain-of-function mutant (Nlrp3A350V). In contrast, hyperglycemic mice with podocyte-specific Nlrp3 or Caspase-1 deficiency showed protection against DKD. Intriguingly, podocyte-specific Nlrp3 deficiency was fully protective, while podocyte-specific caspase-1 deficiency was only partially protective. Podocyte-specific Nlrp3, but not caspase-1 deficiency, maintained glomerular autophagy in hyperglycemic mice, suggesting that podocyte Nlrp3 exerts both canonical and non-canonical effects. Thus, podocyte NLRP3 inflammasome activation is both sufficient and required for DKD and supports the concept that podocytes exert some immune cell-like functions. Hence, as podocyte NLRP3 exerts non-canonical and canonical effects, targeting NLRP3 may be a promising therapeutic approach in DKD.
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Affiliation(s)
- Khurrum Shahzad
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany.
| | - Sameen Fatima
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany; Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - Hamzah Khawaja
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
| | - Ahmed Elwakiel
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
| | - Ihsan Gadi
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
| | - Saira Ambreen
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
| | - Silke Zimmermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
| | - Peter R Mertens
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany
| | - Ronald Biemann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Leipzig, Germany.
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Jha JC, Dai A, Garzarella J, Charlton A, Urner S, Østergaard JA, Okabe J, Holterman CE, Skene A, Power DA, Ekinci EI, Coughlan MT, Schmidt HHHW, Cooper ME, Touyz RM, Kennedy CR, Jandeleit-Dahm K. Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways. Diabetes 2022; 71:1282-1298. [PMID: 35275988 DOI: 10.2337/db21-1079] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/27/2022] [Indexed: 11/13/2022]
Abstract
Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). Here, we provide key findings demonstrating the predominant pathological role of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) in DKD, independent of the previously characterized NOX4 pathway. In patients with diabetes, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors early growth response 1 (EGR-1), protein kinase C-α (PKC-α), and a key metabolic gene involved in redox balance, thioredoxin-interacting protein (TXNIP). In preclinical models of DKD, overexpression of NOX5 in Nox4-deficient mice enhances kidney damage by increasing albuminuria and augmenting renal fibrosis and inflammation via enhanced ROS formation and the modulation of EGR1, TXNIP, ERK1/2, PKC-α, and PKC-ε. In addition, the only first-in-class NOX inhibitor, GKT137831, appears to be ineffective in the presence of NOX5 expression in diabetes. In vitro, silencing of NOX5 in human mesangial cells attenuated upregulation of EGR1, PKC-α, and TXNIP induced by high glucose levels, as well as markers of inflammation (TLR4 and MCP-1) and fibrosis (CTGF and collagens I and III) via reduction in ROS formation. Collectively, these findings identify NOX5 as a superior target in human DKD compared with other NOX isoforms such as NOX4, which may have been overinterpreted in previous rodent studies.
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Affiliation(s)
- Jay C Jha
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Aozhi Dai
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Jessica Garzarella
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Amelia Charlton
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Sofia Urner
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University, Dusseldorf, Germany
| | - Jakob A Østergaard
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Jun Okabe
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Chet E Holterman
- Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Alison Skene
- Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia
| | - David A Power
- Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia
| | - Elif I Ekinci
- Department of Medicine, Austin Health, University of Melbourne, Parkville, Victoria, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Harald H H W Schmidt
- Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Mark E Cooper
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Chris R Kennedy
- Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Karin Jandeleit-Dahm
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University, Dusseldorf, Germany
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Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol 2022; 18:361-377. [PMID: 35190716 PMCID: PMC9832386 DOI: 10.1038/s41581-022-00540-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2022] [Indexed: 01/13/2023]
Abstract
Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.
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Affiliation(s)
- Kenneth I Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Scienter Center, Memphis, TN, USA.
| | - Santosh L Saraf
- Division of Hematology/Oncology, University of Illinois, Chicago, IL, USA
| | - Vimal K Derebail
- Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, USA
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Zhu BT. Biochemical mechanism underlying the pathogenesis of diabetic retinopathy and other diabetic complications in humans: the methanol-formaldehyde-formic acid hypothesis. Acta Biochim Biophys Sin (Shanghai) 2022; 54:415-451. [PMID: 35607958 PMCID: PMC9828688 DOI: 10.3724/abbs.2022012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022] Open
Abstract
Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
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Affiliation(s)
- Bao Ting Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and DevelopmentSchool of MedicineThe Chinese University of Hong KongShenzhen518172China
- Department of PharmacologyToxicology and TherapeuticsSchool of MedicineUniversity of Kansas Medical CenterKansas CityKS66160USA
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Mechanisms of podocyte injury and implications for diabetic nephropathy. Clin Sci (Lond) 2022; 136:493-520. [PMID: 35415751 PMCID: PMC9008595 DOI: 10.1042/cs20210625] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/25/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023]
Abstract
Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.
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IGFBP5 promotes diabetic kidney disease progression by enhancing PFKFB3-mediated endothelial glycolysis. Cell Death Dis 2022; 13:340. [PMID: 35418167 PMCID: PMC9007962 DOI: 10.1038/s41419-022-04803-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/15/2022] [Accepted: 03/30/2022] [Indexed: 12/16/2022]
Abstract
Renal inflammation is a critical pathophysiological characteristic of diabetic kidney disease (DKD). The mechanism of the inflammatory response is complicated, and there are few effective treatments for renal inflammation that can be used clinically. Insulin-like growth factor-binding protein 5 (IGFBP5) is an important secretory protein that is related to inflammation and fibrosis in several tissues. Studies have shown that the IGFBP5 level is significantly upregulated in DKD. However, the function of IGFBP5 and its mechanism in DKD remain unclear. Here, we showed that IGFBP5 levels were significantly increased in the kidneys of diabetic mice. Ablation of IGFBP5 alleviated kidney inflammation in DKD mice. Mechanistically, IGFBP5 increased glycolysis, which was characterized by increases in lactic acid and the extracellular acidification rate, by activating the transcription factor early growth response 1 (EGR1) and enhancing the expression of PFKFB3 in endothelial cells. Furthermore, a mutation in PFKFB3 attenuated renal inflammation in DKD mice. Taken together, we provided evidence that IGFBP5 enhanced kidney inflammation through metabolic reprogramming of glomerular endothelial cells. Our results provide new mechanistic insights into the effect of IGFBP5 on kidney and highlight potential therapeutic opportunities for IGFBP5 and the metabolic regulators involved in DKD. ![]()
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Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy. Acta Pharmacol Sin 2022; 43:659-671. [PMID: 34103688 PMCID: PMC8888565 DOI: 10.1038/s41401-021-00689-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/26/2021] [Indexed: 02/05/2023]
Abstract
Tubulointerstitial inflammation plays an important role in the progression of diabetic nephropathy (DN), and tubular epithelial cells (TECs) are crucial promoters of the inflammatory cascade. Exchange protein activated by cAMP (Epac) has been shown to suppress the angiotensin II (Ang-II)-induced release of inflammatory cytokines in tubular cells. However, the role of Epac in TEC-mediated tubulointerstitial inflammation in DN remains unknown. We found that administering the Epac agonist 8-pCPT-2'-O-Me-cAMP (8-O-cAMP) to db/db mice inhibited tubulointerstitial inflammation characterized by macrophage infiltration and increased inflammatory cytokine release and consequently alleviated tubulointerstitial fibrosis in the kidney. Furthermore, 8-O-cAMP administration restored CCAAT/enhancer binding protein β (C/EBP-β) expression and further upregulated the expression of Suppressor of cytokine signaling 3 (SOCS3), while inhibiting p-STAT3, MCP-1, IL-6, and TNF-α expression in the kidney cortex in db/db mice. And in vitro study showed that macrophage migration and MCP-1 expression induced by high glucose (HG, 30 mM) were notably reduced by 8-O-cAMP in human renal proximal tubule epithelial (HK-2) cells. In addition, 8-O-cAMP treatment restored C/EBP-β expression in HK-2 cells and promoted C/EBP-β translocation to the nucleus, where it transcriptionally upregulated SOCS3 expression, subsequently inhibiting STAT3 phosphorylation. Under HG conditions, siRNA-mediated knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on the release of MCP-1. In contrast, SOCS3 overexpression inhibited HG-induced activation of STAT3 and MCP-1 expression in HK-2 cells. These findings indicate that Epac activation via 8-O-cAMP ameliorates tubulointerstitial inflammation in DN through the C/EBP-β/SOCS3/STAT3 pathway.
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Bell RMB, Conway BR. Macrophages in the kidney in health, injury and repair. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 367:101-147. [PMID: 35461656 DOI: 10.1016/bs.ircmb.2022.01.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Macrophages are a key component of the renal mononuclear phagocyte system, playing a major role in defense against infection, renal injury and repair. Yolk sac macrophage precursors seed the early embryonic kidney and are important for renal development. Later, renal macrophages are derived from hematopoietic stem cells and in adult life, there is a significant contribution from circulating monocytes, which is enhanced in response to infection or injury. Macrophages are highly plastic and can alter their phenotype in response to cues from parenchymal renal cells. Danger-associated molecules released from injured kidney cells may activate macrophages toward a pro-inflammatory phenotype, mediating further recruitment of inflammatory cells, exacerbating renal injury and activating renal fibroblasts to promote scarring. In acute kidney injury, once the injury stimulus has abated, macrophages may adopt a more reparative phenotype, dampening the immune response and promoting repair of renal tissue. However, in chronic kidney disease ongoing activation of pro-inflammatory monocytes and persistence of reparative macrophages leads to glomerulosclerosis and tubulointerstitial fibrosis, the hallmarks of end-stage kidney disease. Several strategies to inhibit the recruitment, activation and secretory products of pro-inflammatory macrophages have proven beneficial in pre-clinical models and are now undergoing clinical trials in patients with kidney disease. In addition, macrophages may be utilized in cell therapy as a "Trojan Horse" to deliver targeted therapies to the kidney. Single-cell RNA sequencing has identified a previously unappreciated spectrum of macrophage phenotypes, which may be selectively present in injury or repair, and ongoing functional analyses of these subsets may identify more specific targets for therapeutic intervention.
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Affiliation(s)
- Rachel M B Bell
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Bryan R Conway
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
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Ma T, Li X, Zhu Y, Yu S, Liu T, Zhang X, Chen D, Du S, Chen T, Chen S, Xu Y, Fan Q. Excessive Activation of Notch Signaling in Macrophages Promote Kidney Inflammation, Fibrosis, and Necroptosis. Front Immunol 2022; 13:835879. [PMID: 35280997 PMCID: PMC8913942 DOI: 10.3389/fimmu.2022.835879] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/17/2022] [Indexed: 12/24/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD). Existing treatments cannot control the progression of diabetic nephropathy very well. In diabetic nephropathy, Many monocytes and macrophages infiltrate kidney tissue. However, the role of these cells in the pathogenesis of diabetic nephropathy has not been fully elucidated. In this study, we analyzed patient kidney biopsy specimens, diabetic nephropathy model animals. Meanwhile, we cocultured cells and found that in diabetic nephropathy, damaged intrinsic renal cells (glomerular mesangial cells and renal tubular epithelial cells) recruited monocytes/macrophages to the area of tissue damage to defend against and clear cell damage. This process often involved the activation of different types of macrophages. Interestingly, the infiltrating macrophages were mainly M1 (CD68+iNOS+) macrophages. In diabetic nephropathy, crosstalk between the Notch pathway and NF-κB signaling in macrophages contributed to the polarization of macrophages. Hyperpolarized macrophages secreted large amounts of inflammatory cytokines and exacerbated the inflammatory response, extracellular matrix secretion, fibrosis, and necroptosis of intrinsic kidney cells. Additionally, macrophage depletion therapy with clodronate liposomes and inhibition of the Notch pathway in macrophages alleviated the pathological changes in kidney cells. This study provides new information regarding diabetic nephropathy-related renal inflammation, the causes of macrophage polarization, and therapeutic targets for diabetic nephropathy.
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Affiliation(s)
- Tiankui Ma
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Xin Li
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
- Department of Nephrology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yonghong Zhu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Shufan Yu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Tianyan Liu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Xiaodan Zhang
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Dong Chen
- Department of Centre Laboratory, The First Hospital of China Medical University, Shenyang, China
| | - Shuyan Du
- Department of Centre Laboratory, The First Hospital of China Medical University, Shenyang, China
| | - Tong Chen
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Shuo Chen
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Yanyan Xu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
- Department of Nephrology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Qiuling Fan
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
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Kong L, Andrikopoulos S, MacIsaac RJ, Mackay LK, Nikolic‐Paterson DJ, Torkamani N, Zafari N, Marin ECS, Ekinci EI. Role of the adaptive immune system in diabetic kidney disease. J Diabetes Investig 2022; 13:213-226. [PMID: 34845863 PMCID: PMC8847140 DOI: 10.1111/jdi.13725] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/19/2021] [Accepted: 11/28/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end-stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro-inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon-γ and tumor necrosis factor-α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.
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Affiliation(s)
- Lingyun Kong
- Department of MedicineAustin Health, University of MelbourneMelbourneVictoriaAustralia
| | | | - Richard J MacIsaac
- Department of MedicineAustin Health, University of MelbourneMelbourneVictoriaAustralia
- Department of Endocrinology & DiabetesSt Vincent's Hospital MelbourneMelbourneVictoriaAustralia
| | - Laura K Mackay
- Department of Microbiology and ImmunologyPeter Doherty Institute for Infection and ImmunityThe University of MelbourneMelbourneVictoriaAustralia
| | - David J Nikolic‐Paterson
- Department of NephrologyMonash Medical Center and Monash University Center for Inflammatory DiseasesMelbourneVictoriaAustralia
| | - Niloufar Torkamani
- Department of MedicineAustin Health, University of MelbourneMelbourneVictoriaAustralia
- Endocrine Center of ExcellenceAustin HealthMelbourneVictoriaAustralia
| | - Neda Zafari
- Department of MedicineAustin Health, University of MelbourneMelbourneVictoriaAustralia
| | - Evelyn C S Marin
- College of Sport and Exercise ScienceVictoria UniversityMelbourneVictoriaAustralia
| | - Elif I Ekinci
- Department of MedicineAustin Health, University of MelbourneMelbourneVictoriaAustralia
- Endocrine Center of ExcellenceAustin HealthMelbourneVictoriaAustralia
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Lin X, Lei XQ, Yang JK, Jia J, Zhong X, Tan RZ, Wang L. Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) improves renal mesangial cell damage in diabetic nephropathy by inhibiting the inflammatory response of infiltrated macrophages. BMC Complement Med Ther 2022; 22:17. [PMID: 35057768 PMCID: PMC8781170 DOI: 10.1186/s12906-021-03477-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 12/03/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease with scantly effective treatment. Numerous evidences indicated that macrophages play an important role in the occurrence and pathogenesis of DN by secreting inflammatory cytokines. Mincle is mainly expressed in macrophages and promotes kidney inflammation and damage of acute kidney injury. However, the role of Mincle in DN is unclear. In this study, we aim to investigate the effect of Mincle-related macrophage inflammation on DN, and whether it can be identified as the therapeutic target for Astragalus mongholicus Bunge and Panax notoginseng Formula (A&P), a widely used Chinese herbal decoction for DN treatment. METHODS In vivo experiments high-fat and high-sugar diet and streptozotocin was used to establish a diabetic nephropathy model, while in vitro experiments inflammation model was induced by high-glucose in mouse Bone Marrow-Derived Macrophages (BMDM) cells and mouse mesangial (MES) cells. Kidney pathological staining is used to detect kidney tissue damage and inflammation, Western blotting, Real-time PCR and ELISA are performed to detect Mincle signaling pathway related proteins and inflammatory cytokines. RESULTS Mincle was mainly expressed in infiltrated macrophage of DN kidney, and was significant decreased after A&P administration. The in vitro experiments also proved that A&P effectively down-regulated the expression of Mincle in macrophage stimulated by high glucose. Meanwhile, the data demonstrated that A&P can reduce the activation of NFκB, and the expression and secretion of inflammatory cytokines in DN kidney or BMDM cells. Notably, we set up a co-culture system to conform that BMDM cells can aggravate the inflammatory response of mesangial (MES) cells under high glucose stimulation. Furthermore, we found that the anti-injury role of A&P in MES cells was dependent on inhibition of the Mincle in macrophage. CONCLUSION In summary, our study found that A&P is effective in reducing renal pathological damage and improving renal function and inflammation in diabetic nephropathy by a mechanism mainly related to the inhibition of the Mincle/Card9/NFκB signaling pathway.
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Affiliation(s)
- Xiao Lin
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China
| | - Xiao-Qin Lei
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China
| | - Jie-Ke Yang
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China
| | - Jian Jia
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China
| | - Xia Zhong
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China
| | - Rui-Zhi Tan
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China.
| | - Li Wang
- Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, 319# zhongshan road, Luzhou, 646000, Sichuan, China.
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Jiang S, Luo M, Bai X, Nie P, Zhu Y, Cai H, Li B, Luo P. Cellular crosstalk of glomerular endothelial cells and podocytes in diabetic kidney disease. J Cell Commun Signal 2022; 16:313-331. [PMID: 35041192 DOI: 10.1007/s12079-021-00664-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes and is the leading cause of end-stage renal disease (ESRD). Persistent proteinuria is an important feature of DKD, which is caused by the destruction of the glomerular filtration barrier (GFB). Glomerular endothelial cells (GECs) and podocytes are important components of the GFB, and their damage can be observed in the early stages of DKD. Recently, studies have found that crosstalk between cells directly affects DKD progression, which has prospective research significance. However, the pathways involved are complex and largely unexplored. Here, we review the literature on cellular crosstalk of GECs and podocytes in the context of DKD, and highlight specific gaps in the field to propose future research directions. Elucidating the intricates of such complex processes will help to further understand the pathogenesis of DKD and develop better prevention and treatment options.
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Affiliation(s)
- Shan Jiang
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Manyu Luo
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Xue Bai
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Ping Nie
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Yuexin Zhu
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Hangxi Cai
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China
| | - Bing Li
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China.
| | - Ping Luo
- Department of Nephrology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Changchun, 130041, China.
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