|
1
|
Li K, Tang H, Cao X, Zhang X, Wang X. PTEN: A Novel Diabetes Nephropathy Protective Gene Related to Cellular Senescence. Int J Mol Sci 2025; 26:3088. [PMID: 40243723 PMCID: PMC11988946 DOI: 10.3390/ijms26073088] [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: 02/15/2025] [Revised: 03/20/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The current diagnostic and therapeutic approaches need to be improved. Cellular senescence has been implicated in the pathogenesis of DN, but its precise role remains unclear. This study aimed to identify key pathogenic genes related to cellular senescence in DN and explore their potential as diagnostic biomarkers. Using transcriptomic data from GEO datasets (GSE96804, GSE30122, GSE142025, and GSE104948) and cellular senescence-related genes sourced from the GenAge database, we integrated multiple bioinformatics approaches, including differential expression analysis, weighted gene co-expression network analysis (WGCNA), machine learning and protein-protein interaction (PPI), to identify diagnostic genes. PTEN was identified as a key diagnostic gene. Immune infiltration analysis revealed that PTEN expression is positively correlated with macrophage M2 and dendritic cell resting infiltration and negatively correlated with monocytes and neutrophils. snRNA analysis revealed that PTEN is mainly expressed in mesangial cells. Finally, RT-PCR results revealed that the mRNA expression of PTEN was upregulated in kidneys from db/db mice. Additionally, high-glucose treatment significantly upregulated PTEN expression in cultured human mesangial cells. This study identifies PTEN as a potential diagnostic biomarker for DN which may contribute to early detection and personalized therapeutic strategies.
Collapse
Affiliation(s)
- Kang Li
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China
| | - Huidi Tang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China
| | - Xiaoqing Cao
- Department of Cardiology, Shandong Public Health Clinical Center, Shandong University, Jinan 250013, China
| | - Xiaoli Zhang
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China
| | - Xiaojie Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China
| |
Collapse
|
|
2
|
Manoj H, Gomes SM, Thimmappa PY, Nagareddy PR, Jamora C, Joshi MB. Cytokine signalling in formation of neutrophil extracellular traps: Implications for health and diseases. Cytokine Growth Factor Rev 2025; 81:27-39. [PMID: 39681501 DOI: 10.1016/j.cytogfr.2024.12.001] [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: 11/09/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024]
Abstract
Neutrophils, as essential component of the innate immune response, form a crucial part in the defence mechanisms through the release of extracellular traps (NETs). These web-like structures, composed of chromatin and antimicrobial proteins, are essential for the entrapment and inactivation of pathogens. However, either constitutive formation or inefficient clearance of NETs leads to adverse effects such as fibrosis, thrombosis, delayed wound healing and tissue damage in multiple diseases associated with sterile inflammation. This dichotomy casts NETs as both protective agents and harmful factors in several diseases such as autoimmune diseases, metabolic syndromes, systemic infections, and malignancies. Besides microbes and their products, variety of stimulants including pro-inflammatory cytokines induce NETs. The complex interactions and cross talk among the pro-inflammatory cytokines including IL-8, IL-6, GM-CSF, TNF-α, IFNs, and IL-1β activate neutrophils to form NETs and also contributes to a vicious circle of inflammatory cascade, leading to increased inflammation, oxidative stress, and thrombotic events. Emerging evidence indicates that the dysregulated cytokine milieus in diseases, such as diabetes mellitus, obesity, atherosclerosis, stroke, rheumatoid arthritis, and systemic lupus erythematosus, potentiate NETs release, thereby promoting disease development. Thus, neutrophils represent both critical effectors and potential therapeutic targets, underscoring their importance in the context of cytokine-mediated therapies for a spectrum of diseases. In the present review, we describe various cytokines and associated signalling pathways activating NETs formation in different human pathologies. Further, the review identifies potential strategies to pharmacologically modulate cytokine pathways to reduce NETs.
Collapse
Affiliation(s)
- Haritha Manoj
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sarah Michael Gomes
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Pooja Yedehalli Thimmappa
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Prabhakara R Nagareddy
- Department of Internal Medicine, Section of Cardiovascular Diseases, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma, OK, USA
| | - Colin Jamora
- Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, Uttar Pradesh 201314, India
| | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
| |
Collapse
|
|
3
|
Zhang T, Widdop RE, Ricardo SD. Transition from acute kidney injury to chronic kidney disease: mechanisms, models, and biomarkers. Am J Physiol Renal Physiol 2024; 327:F788-F805. [PMID: 39298548 DOI: 10.1152/ajprenal.00184.2024] [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: 06/26/2024] [Revised: 08/15/2024] [Accepted: 09/01/2024] [Indexed: 09/22/2024] Open
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected conditions with overlapping pathophysiological mechanisms. This review examines the transition from AKI to CKD, focusing on the molecular mechanisms, animal models, and biomarkers essential for understanding and managing this progression. AKI often progresses to CKD due to maladaptive repair processes, persistent inflammation, and fibrosis, with both conditions sharing common pathways involving cell death, inflammation, and extracellular matrix (ECM) deposition. Current animal models, including ischemia-reperfusion injury (IRI) and nephrotoxic damage, help elucidate these mechanisms but have limitations in replicating the complexity of human disease. Emerging biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and soluble tumor necrosis factor receptors (TNFRs) show promise in early detection and monitoring of disease progression. This review highlights the need for improved animal models and biomarker validation to better mimic human disease and enhance clinical translation. Advancing our understanding of the AKI-to-CKD transition through targeted therapies and refined research approaches holds the potential to significantly improve patient outcomes.
Collapse
Affiliation(s)
- Tingfang Zhang
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Robert E Widdop
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Sharon D Ricardo
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| |
Collapse
|
|
4
|
Zoccali C, Tripepi G, Stel V, Fu EL, Mallamaci F, Dekker F, Jager KJ. Decoy receptors as biomarkers for exploring aetiology and designing new therapies. Clin Kidney J 2024; 17:sfae222. [PMID: 39184952 PMCID: PMC11341986 DOI: 10.1093/ckj/sfae222] [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: 04/02/2024] [Indexed: 08/27/2024] Open
Abstract
Soluble decoy receptors (DR) are circulating proteins that act as molecular traps for ligands that modulate various signalling pathways. These proteins can be exploited as biomarkers and, in some cases, as drugs in various disease contexts. Inflammation is a key area where DRs have shown significant potential. By binding to pro-inflammatory cytokines, inflammatory DRs, such as soluble tumour necrosis factor receptors (sTNFRs), can inhibit downstream inflammatory signalling. This modulation of the inflammatory response holds promise for therapeutic interventions in various inflammatory conditions, including cardiovascular and chronic kidney diseases. Soluble DRs for advanced glycation end products (sRAGE) bind to advanced glycation end products (AGEs), reducing their detrimental effects on vascular function and atherosclerosis. High circulating sRAGE levels are associated with a lower risk for CV events, highlighting the potential of these soluble receptors for assessing the role of AGEs in CV diseases and managing the attendant risk. DRs may serve as biomarkers and therapeutic agents to advance our understanding of disease mechanisms and improve patients' outcomes. Their ability to modulate signalling pathways in a controlled manner opens up new opportunities for therapeutic interventions in various diseases, ranging from inflammation to cardiovascular and renal disorders.
Collapse
Affiliation(s)
- Carmine Zoccali
- Renal Research Institute, NY, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Giovanni Tripepi
- CNR-IFC, Institute of Clinical Physiology, Research Unit of Clinical Epidemiology, Reggio Calabria, Italy
| | - Vianda Stel
- ERA Registry, Amsterdam UMC location and the University of Amsterdam, Department of Medical Informatics, Amsterdam, the Netherlands
- Amsterdam Public Health, Quality of Care, Amsterdam, the Netherlands
| | - Edouard L Fu
- Fresenius Medical Care, Global Medical Office, Crema, Italy
| | - Francesca Mallamaci
- CNR-IFC, Institute of Clinical Physiology, Research Unit of Clinical Epidemiology, Reggio Calabria, Italy
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Friedo Dekker
- Fresenius Medical Care, Global Medical Office, Crema, Italy
| | - Kitty J Jager
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
- Nephrology, Dialysis and Transplantation Unit, Azienda Ospedaliera “Bianchi-Melacrino-Morelli” Grande Ospedale Metropolitano of Reggio Calabria, Italy
| |
Collapse
|
|
5
|
Wang L, Su J, Liu Z, Ding S, Li Y, Hou B, Hu Y, Dong Z, Tang J, Liu H, Liu W. Identification of immune-associated biomarkers of diabetes nephropathy tubulointerstitial injury based on machine learning: a bioinformatics multi-chip integrated analysis. BioData Min 2024; 17:20. [PMID: 38951833 PMCID: PMC11218417 DOI: 10.1186/s13040-024-00369-x] [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: 01/17/2024] [Accepted: 06/10/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN. METHODS The gene chip data were retrieved from the GEO database using the search term ' diabetic nephropathy '. The ' limma ' software package was used to identify differentially expressed genes (DEGs) between DN and control samples. Gene set enrichment analysis (GSEA) was performed on genes obtained from the molecular characteristic database (MSigDB. The R package 'WGCNA' was used to identify gene modules associated with tubulointerstitial injury in DN, and it was crossed with immune-related DEGs to identify target genes. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on differentially expressed genes using the 'ClusterProfiler' software package in R. Three methods, least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest (RF), were used to select immune-related biomarkers for diagnosis. We retrieved the tubulointerstitial dataset from the Nephroseq database to construct an external validation dataset. Unsupervised clustering analysis of the expression levels of immune-related biomarkers was performed using the 'ConsensusClusterPlus 'R software package. The urine of patients who visited Dongzhimen Hospital of Beijing University of Chinese Medicine from September 2021 to March 2023 was collected, and Elisa was used to detect the mRNA expression level of immune-related biomarkers in urine. Pearson correlation analysis was used to detect the effect of immune-related biomarker expression on renal function in DN patients. RESULTS Four microarray datasets from the GEO database are included in the analysis : GSE30122, GSE47185, GSE99340 and GSE104954. These datasets included 63 DN patients and 55 healthy controls. A total of 9415 genes were detected in the data set. We found 153 differentially expressed immune-related genes, of which 112 genes were up-regulated, 41 genes were down-regulated, and 119 overlapping genes were identified. GO analysis showed that they were involved in various biological processes including leukocyte-mediated immunity. KEGG analysis showed that these target genes were mainly involved in the formation of phagosomes in Staphylococcus aureus infection. Among these 119 overlapping genes, machine learning results identified AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1 and FSTL1 as potential tubulointerstitial immune-related biomarkers. External validation suggested that the above markers showed diagnostic efficacy in distinguishing DN patients from healthy controls. Clinical studies have shown that the expression of AGR2, CX3CR1 and FSTL1 in urine samples of DN patients is negatively correlated with GFR, the expression of CX3CR1 and FSTL1 in urine samples of DN is positively correlated with serum creatinine, while the expression of DEFB1 in urine samples of DN is negatively correlated with serum creatinine. In addition, the expression of CX3CR1 in DN urine samples was positively correlated with proteinuria, while the expression of DEFB1 in DN urine samples was negatively correlated with proteinuria. Finally, according to the level of proteinuria, DN patients were divided into nephrotic proteinuria group (n = 24) and subrenal proteinuria group. There were significant differences in urinary AGR2, CCR2 and DEFB1 between the two groups by unpaired t test (P < 0.05). CONCLUSIONS Our study provides new insights into the role of immune-related biomarkers in DN tubulointerstitial injury and provides potential targets for early diagnosis and treatment of DN patients. Seven different genes ( AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1, FSTL1 ), as promising sensitive biomarkers, may affect the progression of DN by regulating immune inflammatory response. However, further comprehensive studies are needed to fully understand their exact molecular mechanisms and functional pathways in DN.
Collapse
Affiliation(s)
- Lin Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Jiaming Su
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhongjie Liu
- Beijing University of Chinese Medicine, Beijing, China
| | - Shaowei Ding
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yaotan Li
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Baoluo Hou
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yuxin Hu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhaoxi Dong
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Tang
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Hongfang Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China.
| | - Weijing Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital, Affiliated to Beijing University of Chinese Medicine, Beijing, China.
- Beijing University of Chinese Medicine, Beijing, China.
| |
Collapse
|
|
6
|
Liang LL, He MF, Zhou PP, Pan SK, Liu DW, Liu ZS. GSK3β: A ray of hope for the treatment of diabetic kidney disease. FASEB J 2024; 38:e23458. [PMID: 38315453 DOI: 10.1096/fj.202302160r] [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: 10/23/2023] [Revised: 12/09/2023] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3β (glycogen synthase kinase 3β), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3β participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3β in DKD and its damage mechanism in different intrinsic renal cells. GSK3β is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3β inhibitors on DKD are also discussed.
Collapse
Affiliation(s)
- Lu-Lu Liang
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Meng-Fei He
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Pan-Pan Zhou
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Shao-Kang Pan
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Dong-Wei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Zhang-Suo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| |
Collapse
|
|
7
|
Uemura T, Nishimoto M, Eriguchi M, Tamaki H, Tasaki H, Furuyama R, Fukata F, Kosugi T, Morimoto K, Matsui M, Samejima KI, Tsuruya K. Utility of serum β2-microglobulin for prediction of kidney outcome among patients with biopsy-proven diabetic nephropathy. Diabetes Obes Metab 2024; 26:583-591. [PMID: 37921072 DOI: 10.1111/dom.15347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/05/2023] [Accepted: 10/15/2023] [Indexed: 11/04/2023]
Abstract
AIM To examine whether serum β2-microglobulin (β2-MG) could improve the prediction performance for kidney failure with replacement therapy (KFRT) among patients with diabetic nephropathy (DN). METHODS Patients with biopsy-proven DN at Nara Medical University Hospital were included. The exposure of interest was log-transformed serum β2-MG levels measured at kidney biopsy. The outcome variable was KFRT. Multivariable Cox regression models and competing-risk regression models, with all-cause mortality as a competing event, were performed. Model fit by adding serum β2-MG levels was calculated using the Akaike information criterion (AIC). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indexes were used to evaluate the improvement of predictive performance for 5-year cumulative incidence of KFRT by serum β2-MG levels. RESULTS Among 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. A higher serum β2-MG level (1-unit increase in log-transformed serum β2-MG level) was associated with a higher incidence of KFRT, even after adjustments for previously known clinical and histological risk factors (hazard ratio [95% confidence interval {CI}]: 3.30 [1.57-6.94] and subdistribution hazard ratio [95% CI]: 3.07 [1.55-6.06]). The addition of log-transformed serum β2-MG level reduced AIC and improved the prediction of KFRT (NRI and IDI: 0.32 [0.09-0.54] and 0.03 [0.01-0.56], respectively). CONCLUSIONS Among patients with biopsy-proven DN, serum β2-MG was an independent predictor of KFRT and improved prediction performance. In addition to serum creatinine, serum β2-MG should probably be measured for DN.
Collapse
Affiliation(s)
- Takayuki Uemura
- Department of Nephrology, Nara Medical University, Nara, Japan
| | | | | | - Hiroyuki Tamaki
- Department of Nephrology, Nara Medical University, Nara, Japan
| | - Hikari Tasaki
- Department of Nephrology, Nara Medical University, Nara, Japan
| | - Riri Furuyama
- Department of Nephrology, Nara Medical University, Nara, Japan
| | - Fumihiro Fukata
- Department of Nephrology, Yamatotakada Municipal Hospital, Nara, Japan
| | - Takaaki Kosugi
- Department of Nephrology, Nara Medical University, Nara, Japan
| | - Katsuhiko Morimoto
- Department of Nephrology, Nara Prefecture Seiwa Medical Center, Nara, Japan
| | - Masaru Matsui
- Department of Nephrology, Nara Medical University, Nara, Japan
- Department of Nephrology, Nara Prefecture General Medical Center, Nara, Japan
| | | | | |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
Mishra B, Tiwari A, Mishra S. Metabolic Changes and Immunity Suppression Parameters as Biomarkers of Environmental Pollutants. BIOMONITORING OF POLLUTANTS IN THE GLOBAL SOUTH 2024:693-719. [DOI: 10.1007/978-981-97-1658-6_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
10
|
Yan J, Li X, Liu N, He JC, Zhong Y. Relationship between Macrophages and Tissue Microenvironments in Diabetic Kidneys. Biomedicines 2023; 11:1889. [PMID: 37509528 PMCID: PMC10377233 DOI: 10.3390/biomedicines11071889] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/23/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Increasing evidence has suggested that inflammation is a key microenvironment involved in the development and progression of DN. Studies have confirmed that macrophage accumulation is closely related to the progression to human DN. Macrophage phenotype is highly regulated by the surrounding microenvironment in the diabetic kidneys. M1 and M2 macrophages represent distinct and sometimes coexisting functional phenotypes of the same population, with their roles implicated in pathological changes, such as in inflammation and fibrosis associated with the stage of DN. Recent findings from single-cell RNA sequencing of macrophages in DN further confirmed the heterogeneity and plasticity of the macrophages. In addition, intrinsic renal cells interact with macrophages directly or through changes in the tissue microenvironment. Macrophage depletion, modification of its polarization, and autophagy could be potential new therapies for DN.
Collapse
Affiliation(s)
- Jiayi Yan
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xueling Li
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ni Liu
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - John Cijiang He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yifei Zhong
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| |
Collapse
|
|
11
|
Moin H, Shafi R, Ishtiaq A, Liaquat A, Majeed S, Zaidi NN. Effectiveness of analog of Humanin in ameliorating streptozotocin-induced diabetic nephropathy in Sprague Dawley rats. Peptides 2023; 165:171014. [PMID: 37119975 DOI: 10.1016/j.peptides.2023.171014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/01/2023]
Abstract
Diabetes mellitus(DM) is associated with numerous complications, including nephropathy, which principally occur due to hyperglycemia-induced oxidative stress and inflammation. Humanin(HN), a novel peptide generated from mitochondria, has anti-oxidant and anti-inflammatory potential as observed in different disease models. However, role of HN in diabetic nephropathy (DN) has not yet been explored. This study aimed to evaluate biochemical and molecular aspects of the effects of HN analog, Humanin-glycine([S14G]-humanin) on streptozotocin (STZ)-induced rat model of DN. Ninety Sprague Dawley (SD) rats were randomly segregated into three groups - A (control), B (disease control) and C (treatment). DM type-I was induced in group B and C via single intra-peritoneal dose of STZ (45mg/Kg). Seven days following STZ injection, rats were deemed diabetic if their blood glucose level was >250mg/dL. Subsequently, diabetic rats in group C were injected with [S14G]-humanin intra-peritoneally (0.4mg/Kg/day) for sixteen weeks. Biochemical analysis revealed that diabetic rats had markedly elevated levels of serum glucose, creatinine, BUN, TNF-α, and kidney tissue SOD. Whereas, significant decline was detected in serum insulin and albumin levels. All these parameters were significantly reversed in group C after administering [S14G]-humanin. Moreover, qRT-PCR analysis displayed up-regulation of pro-inflammatory (IL-18, IL-6, IL-1α, IL-1β, TNF-α) and down-regulation of anti-inflammatory cytokines (IL-10, IL-1RN, IL-4) in diabetic rats (group B). [S14G]-humanin treatment significantly reversed the expression IL-18 and IL-1α, however, change in relative expression of IL-6, IL-1β, TNF-α and anti-inflammatory cytokines was insignificant(group C). Conclusively, the findings of this study depicted potential therapeutic role of [S14G]-humanin in pre-clinical rodent model of DN.
Collapse
Affiliation(s)
- Hira Moin
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Riffat Shafi
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Ayesha Ishtiaq
- Signal Transduction Lab, Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad 45320, Pakistan.
| | - Afrose Liaquat
- Dr. Qamar Alam Research Lab, Department of Biochemistry, Shifa College of Medicine Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Sadaf Majeed
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| | - Nilofar Nasir Zaidi
- Department of Physiology, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad 45550, Pakistan.
| |
Collapse
|
|
12
|
Rico-Fontalvo J, Aroca-Martínez G, Daza-Arnedo R, Cabrales J, Rodríguez-Yanez T, Cardona-Blanco M, Montejo-Hernández J, Rodelo Barrios D, Patiño-Patiño J, Osorio Rodríguez E. Novel Biomarkers of Diabetic Kidney Disease. Biomolecules 2023; 13:biom13040633. [PMID: 37189380 DOI: 10.3390/biom13040633] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 04/03/2023] Open
Abstract
Diabetic kidney disease (DKD) is a highly prevalent condition worldwide. It represents one of the most common complications arising from diabetes mellitus (DM) and is the leading cause of end-stage kidney disease (ESKD). Its development involves three fundamental components: the hemodynamic, metabolic, and inflammatory axes. Clinically, persistent albuminuria in association with a progressive decline in glomerular filtration rate (GFR) defines this disease. However, as these alterations are not specific to DKD, there is a need to discuss novel biomarkers arising from its pathogenesis which may aid in the diagnosis, follow-up, therapeutic response, and prognosis of the disease.
Collapse
|
|
13
|
Ding S, Yang Y, Zheng Y, Xu J, Cheng Y, Wei W, Yu F, Li L, Li M, Wang M, Wang Z, Xiang G. Diagnostic Value of the Combined Measurement of Serum HCY and NRG4 in Type 2 Diabetes Mellitus with Early Complicating Diabetic Nephropathy. J Pers Med 2023; 13:jpm13030556. [PMID: 36983737 PMCID: PMC10059699 DOI: 10.3390/jpm13030556] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/16/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
PURPOSE This study aimed to investigate the value of combined detection of HCY and NRG4 in the diagnosis of early diabetic kidney disease (DKD) and to explore the association between the ratio of HCY/NRG4 and DKD. METHODS A total of 140 diabetic patients and 43 healthy people were prospectively enrolled. The plasma HCY level, NRG4 level and HCY/NRG4 of them were measured to compare their differences and analyze the correlation with DKD. The independent influencing factors of patients with DKD were screened, and the nomograph of DKD occurrence was constructed. RESULTS The levels of HCY and HCY/NRG4 in diabetic patients were significantly increased, while the level of NRG4 was significantly decreased (p < 0.01). The AUCs of HCY/NRG4 predicted for DKD were 0.961. HCY/NRG4 and the course of DM were independent risk factors for DKD. A predictive nomograph of DKD was constructed, and decision curve analysis (DCA) showed good clinical application value. HCY/NRG4 was positively correlated with Scr, UACR, TG, UA, BUN, TCHOL and LDL and negatively correlated with eGFR and HDL (p < 0.05). CONCLUSIONS The level of HCY and NRG4 is closely related to the severity of DM, and combined detection of HCY/NRG4 can identify patients with DKD at an early stage.
Collapse
Affiliation(s)
- Sheng Ding
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan 430070, China
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Yi Yang
- Department of Radiology, The First Wuhan Hospital, Wuhan 430022, China
| | - Yuming Zheng
- Department of Physical Examination, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Jinling Xu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan 430070, China
| | - Yangyang Cheng
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan 430070, China
| | - Wei Wei
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan 430070, China
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Fuding Yu
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Li Li
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Menglan Li
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Mengjie Wang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Zhongjing Wang
- Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Guangda Xiang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Endocrinology, General Hospital of Central Theater Command, Wuluo Road 627, Wuhan 430070, China
| |
Collapse
|
|
14
|
Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease. Pharmacol Res 2023; 190:106710. [PMID: 36871895 DOI: 10.1016/j.phrs.2023.106710] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023]
Abstract
Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD.
Collapse
|
|
15
|
Fu J, Sun Z, Wang X, Zhang T, Yuan W, Salem F, Yu SMW, Zhang W, Lee K, He JC. The single-cell landscape of kidney immune cells reveals transcriptional heterogeneity in early diabetic kidney disease. Kidney Int 2022; 102:1291-1304. [PMID: 36108806 PMCID: PMC9691617 DOI: 10.1016/j.kint.2022.08.026] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 08/03/2022] [Accepted: 08/12/2022] [Indexed: 01/12/2023]
Abstract
The pathogenesis of diabetic kidney disease (DKD) involves multifactorial processes that converge to initiate and advance the disease. Although DKD is not typically classified as an inflammatory glomerular disease, mounting evidence supports the involvement of kidney inflammation as a key contributor in DKD pathogenesis, particularly through macrophages. However, detailed identification and corresponding phenotypic changes of macrophages in DKD remain poorly understood. To capture the gene expression changes in specific macrophage cell subsets in early DKD, we performed single-cell transcriptomic analysis of CD45-enriched kidney immune cells from type 1 diabetic OVE26 mice at two time points during the disease development. We also undertook a focused analysis of mononuclear phagocytes (macrophages and dendritic cells). Our results show increased resident and infiltrating macrophage subsets in the kidneys of mice with diabetes over time, with heightened expression of pro-inflammatory or anti-inflammatory genes in a subset-specific manner. Further analysis of macrophage polarization states in each subset in the kidneys showed changes consistent with the continuum of activation and differentiation states, with gene expression tending to shift toward undifferentiated phenotypes but with increased M1-like inflammatory phenotypes over time. By deconvolution analysis of RNAseq samples and by immunostaining of biopsies from patients with DKD, we further confirmed a differential expression of select genes in specific macrophage subsets essentially recapitulating the studies in mice. Thus, our study provides a comprehensive analysis of macrophage transcriptomic profiles in early DKD that underscores the dynamic macrophage phenotypes in disease progression.
Collapse
Affiliation(s)
- Jia Fu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Zeguo Sun
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Xuan Wang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Nephrology, Department of Medicine, Shanghai First People Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Tuo Zhang
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA
| | - Weijie Yuan
- Division of Nephrology, Department of Medicine, Shanghai First People Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Fadi Salem
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Samuel Mon-Wei Yu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Program, James J Peters VA Medical Center at Bronx, Bronx, New York, USA.
| |
Collapse
|
|
16
|
Quan W, Wang L. Tripartite motif containing 23 functions as a critical regulator in macrophages to control the pathological feature of diabetic nephropathy. Int Urol Nephrol 2022; 55:1263-1270. [PMID: 36449224 DOI: 10.1007/s11255-022-03419-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Diabetic nephropathy (DN) is a kidney disease resulting from diabetes. Macrophages and macrophage-mediated inflammation contributed to the development of DN. Tripartite motif containing 23 (TRIM23) is E3 ligase and has been involved in inflammation. Until now, the precise roles of TRIM23 in DN are not described yet. Therefore, we evaluated the functions of TRIM23 in DN. METHODS We generated mice with TRIM23 deficiency in macrophages. We also established diabetic mice model. The expression of TRIM23 was measured in diabetic animals. The DN symptoms were compared between diabetic wild-type (WT) mice and TRIM23 conditional knock out mice. The cytokine expression, ubiquitination of TAB2, and interactions between TAB2 and IKK were compared in oxidized low-density lipoprotein (oxLDL) or lipopolysaccharides (LPS)-treated WT and TRIM23-deficient macrophages. RESULTS Upregulation of TRIM23 was observed in diabetic mice and LPS or oxLDL-treated macrophages. Diabetic mice with TRIM23 deficiency in macrophages had attenuated DN symptoms. TRIM23-deficient macrophages had decreased pro-inflammatory cytokines production after oxLDL or LPS stimulation. TRIM23 was predicted to interact with TAB2. The ubiquitination of TAB2 was abolished in oxLDL-treated TRIM23-deficient macrophages, which correlated with decreased activation of IKK. CONCLUSION TRIM23 regulates inflammation in macrophages and plays important role in DN.
Collapse
Affiliation(s)
- Wei Quan
- Department of Endocrinology, Daqing Oilfield General Hospital, No. 9, Zhongkang Street, Sartu District, Daqing, 163000, Heilongjiang, China
| | - Lin Wang
- Department of Endocrinology, Daqing Oilfield General Hospital, No. 9, Zhongkang Street, Sartu District, Daqing, 163000, Heilongjiang, China.
| |
Collapse
|
|
17
|
Jung CY, Yoo TH. Novel biomarkers for diabetic kidney disease. Kidney Res Clin Pract 2022; 41:S46-S62. [DOI: 10.23876/j.krcp.22.084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/17/2022] [Indexed: 11/04/2022] Open
Abstract
Although diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in patients with diabetes mellitus; its prevalence has failed to decline over the past 30 years. To identify those at high risk of developing DKD and disease progression at an early stage, extensive research has been ongoing in the search for prognostic and surrogate endpoint biomarkers for DKD. Although biomarkers are not used routinely in clinical practice or prospective clinical trials, many biomarkers have been developed to improve the early identification and prognostication of patients with DKD. Novel biomarkers that capture one specific mechanism of the DKD disease process have been developed, and studies have evaluated the prognostic value of assay-based biomarkers either in small sets or in combinations involving multiple biomarkers. More recently, several studies have assessed the prognostic value of omics- based biomarkers that include proteomics, metabolomics, and transcriptomics. This review will first describe the biomarkers used in current practice and their limitations, and then summarize the current status of novel biomarkers for DKD with respect to assay- based protein biomarkers, proteomics, metabolomics, and transcriptomics.
Collapse
|
|
18
|
Li HQ, Liu N, Zheng ZY, Teng HL, Pei J. Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice. World J Diabetes 2022; 13:600-612. [PMID: 36159226 PMCID: PMC9412856 DOI: 10.4239/wjd.v13.i8.600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/26/2022] [Accepted: 06/26/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury.
AIM To elucidate whether clopidogrel is beneficial against DN by using a db/db mouse model.
METHODS db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson’s trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1β mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry.
RESULTS Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1β and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice (P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice.
CONCLUSION Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.
Collapse
Affiliation(s)
- Hong-Qin Li
- Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun 130021, Jilin Province, China
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Nian Liu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zong-Yu Zheng
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Hao-Lin Teng
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jin Pei
- Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun 130021, Jilin Province, China
| |
Collapse
|
|
19
|
Tavener SK, Jewell DE, Panickar KS. The Increase in Circulating Levels of Pro-Inflammatory Chemokines, Cytokines, and Complement C5 in Canines with Impaired Kidney Function. Curr Issues Mol Biol 2022; 44:1664-1676. [PMID: 35723372 PMCID: PMC9164022 DOI: 10.3390/cimb44040114] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic low-grade inflammation is a key contributor to the progression of kidney disease. The release of cytokines and other pro-inflammatory proteins may further contribute to detrimental kidney health by increasing interstitial edema and renal fibrosis. The aim of the present study was to investigate the inflammatory markers in canines who developed renal disease naturally and were diagnosed with renal disease either during life or following necropsy, as assessed by a veterinarian. RNA was isolated from canine blood obtained at necropsy and stored as bioarchived samples from ten canines with renal disease (9.6−14.7 yr) and ten controls (10.1−14.8 yr). At the time of death, the mean blood creatinine concentration and BUN were elevated in dogs with renal disease compared to control (both p < 0.01). Samples were assessed for changes in gene expression using the Canine cytokine RT2 Profiler PCR Array for inflammation. There was a significant increase in C-C Motif Chemokine Ligand 16 (CCL16), C-X-C Motif Chemokine Ligand 5 (CXCL5), Interleukin 16 (IL-16), and Complement Component 5 (C5) (all p < 0.05 vs. con). In addition, there was also a statistically non-significant increase in 49 genes and a down-regulation in 35 genes from a panel of total 84 genes. Pro-inflammatory genes including CCL16, CXCL5, IL-16, and C5 can all contribute to renal inflammation and fibrosis through different signaling pathways and may lead to a progressive impairment of kidney function. Blockade of their activation may be important in ameliorating the initiation and/or the progression of renal disease.
Collapse
Affiliation(s)
- Selena K. Tavener
- Science & Technology Center, Hill’s Pet Nutrition, Inc., Topeka, KS 66617, USA;
| | - Dennis E. Jewell
- Department of Grain Science & Industry, Kansas State University, Manhattan, KS 66506, USA;
| | - Kiran S. Panickar
- Science & Technology Center, Hill’s Pet Nutrition, Inc., Topeka, KS 66617, USA;
- Correspondence: ; Tel.: 1-(785)-286-8002
| |
Collapse
|
|
20
|
Jung CY, Yoo TH. Pathophysiologic Mechanisms and Potential Biomarkers in Diabetic Kidney Disease. Diabetes Metab J 2022; 46:181-197. [PMID: 35385633 PMCID: PMC8987689 DOI: 10.4093/dmj.2021.0329] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
Although diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease eventually requiring chronic kidney replacement therapy, the prevalence of DKD has failed to decline over the past 30 years. In order to reduce disease prevalence, extensive research has been ongoing to improve prediction of DKD onset and progression. Although the most commonly used markers of DKD are albuminuria and estimated glomerular filtration rate, their limitations have encouraged researchers to search for novel biomarkers that could improve risk stratification. Considering that DKD is a complex disease process that involves several pathophysiologic mechanisms such as hyperglycemia induced inflammation, oxidative stress, tubular damage, eventually leading to kidney damage and fibrosis, many novel biomarkers that capture one specific mechanism of the disease have been developed. Moreover, the increasing use of high-throughput omic approaches to analyze biological samples that include proteomics, metabolomics, and transcriptomics has emerged as a strong tool in biomarker discovery. This review will first describe recent advances in the understanding of the pathophysiology of DKD, and second, describe the current clinical biomarkers for DKD, as well as the current status of multiple potential novel biomarkers with respect to protein biomarkers, proteomics, metabolomics, and transcriptomics.
Collapse
Affiliation(s)
- Chan-Young Jung
- Department of Internal Medicine and Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine and Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea
- Corresponding author: Tae-Hyun Yoo https://orcid.org/0000-0002-9183-4507 Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea E-mail:
| |
Collapse
|
|
21
|
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.
Collapse
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
| |
Collapse
|
|
22
|
Liu J, Zhang Y, Sheng H, Liang C, Liu H, Moran Guerrero JA, Lu Z, Mao W, Dai Z, Liu X, Zhang L. Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus. Front Immunol 2021; 12:733808. [PMID: 34925317 PMCID: PMC8678409 DOI: 10.3389/fimmu.2021.733808] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/04/2021] [Indexed: 12/29/2022] Open
Abstract
Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.
Collapse
Affiliation(s)
- Jialing Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yanmei Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongqin Sheng
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chunling Liang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Huazhen Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | | | - Zhaoyu Lu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Mao
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhenhua Dai
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Diseases, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xusheng Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Nephrology Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
| |
Collapse
|
|
23
|
Chang LH, Hwu CM, Chu CH, Lin YC, Huang CC, You JY, Chen HS, Lin LY. The combination of soluble tumor necrosis factor receptor type 1 and fibroblast growth factor 21 exhibits better prediction of renal outcomes in patients with type 2 diabetes mellitus. J Endocrinol Invest 2021; 44:2609-2619. [PMID: 33834419 DOI: 10.1007/s40618-021-01568-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/31/2021] [Indexed: 12/16/2022]
Abstract
PURPOSE Numerous biomarkers of diabetic kidney disease (DKD) are associated with renal prognosis but head-to-head comparisons are lacking. This study aimed to examine the association of soluble tumor necrosis factor receptor type 1 (sTNFR1), fibroblast growth factor 21 (FGF-21), endocan, N-terminal pro-brain natriuretic peptide (NT-pro-BNP), and renal outcomes of patients with or without clinical signs of DKD. METHODS A total of 312 patients were enrolled in a prospective observational study that excluded individuals with estimated glomerular filtration rates (eGFR) < 30 mL/min/1.73 m2. Composite renal outcomes included either a > 30% decline in eGFR and worsening albuminuria or both from consecutive tests of blood/urine during a 3.5-year follow-up period. RESULTS Higher sTNFR1 and FGF-21, rather than endocan and NT-pro-BNP, levels were associated with renal outcomes but the significance was lost after adjusting for confounders. However, sTNFR1 levels ≥ 9.79 pg/dL or FGF-21 levels ≥ 1.40 pg/dL were associated with renal outcomes after adjusting for the confounders (hazard ration [HR] 2.76, 95% confidence interval [CI] 1.36-5.60, p = 0.005 for sTNFR1 level; HR 1.95, 95% CI 1.03-3.69, p = 0.03 for FGF-21 level). The combination of both levels exhibited even better association with renal outcomes than did either one alone (adjusted HR 4.45, 95% CI 1.86-10.65, p = 0.001). The results were consistent among patients with preserved renal function and normoalbuminuria. CONCLUSION Both sTNFR1 and FGF-21 levels were associated with renal outcomes of in patients with type 2 diabetes, and the combination of the abovementioned markers exhibits better predictability.
Collapse
Affiliation(s)
- L-H Chang
- Division of Endocrinology and Metabolism, Department of Medicine, Yeezen General Hospital, Taoyuan, Taiwan
- Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan
| | - C-M Hwu
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - C-H Chu
- Department of Otorhinolaryngology-Head and Neck Surgery, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Audiology and Speech Language Pathology, Mackay Medical College, New Taipei City, Taiwan
| | - Y-C Lin
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - C-C Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - J-Y You
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan
| | - H-S Chen
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - L-Y Lin
- Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| |
Collapse
|
|
24
|
Md Dom ZI, Pipino C, Krolewski B, O'Neil K, Satake E, Krolewski AS. Effect of TNFα stimulation on expression of kidney risk inflammatory proteins in human umbilical vein endothelial cells cultured in hyperglycemia. Sci Rep 2021; 11:11133. [PMID: 34045516 PMCID: PMC8160214 DOI: 10.1038/s41598-021-90496-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022] Open
Abstract
We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFα. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFα in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFα-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFα. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes.
Collapse
Affiliation(s)
- Zaipul I Md Dom
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Caterina Pipino
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA.,Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology, University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Bozena Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | | | - Eiichiro Satake
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Andrzej S Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA. .,Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA.
| |
Collapse
|
|
25
|
Petreski T, Piko N, Ekart R, Hojs R, Bevc S. Review on Inflammation Markers in Chronic Kidney Disease. Biomedicines 2021; 9:182. [PMID: 33670423 PMCID: PMC7917900 DOI: 10.3390/biomedicines9020182] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/04/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is one of the major health problems of the modern age. It represents an important public health challenge with an ever-lasting rising prevalence, which reached almost 700 million by the year 2017. Therefore, it is very important to identify patients at risk for CKD development and discover risk factors that cause the progression of the disease. Several studies have tackled this conundrum in recent years, novel markers have been identified, and new insights into the pathogenesis of CKD have been gained. This review summarizes the evidence on markers of inflammation and their role in the development and progression of CKD. It will focus primarily on cytokines, chemokines, and cell adhesion molecules. Nevertheless, further large, multicenter studies are needed to establish the role of these markers and confirm possible treatment options in everyday clinical practice.
Collapse
Affiliation(s)
- Tadej Petreski
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia; (T.P.); (N.P.); (R.H.)
- Department of Internal Medicine and Department of Pharmacology, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
| | - Nejc Piko
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia; (T.P.); (N.P.); (R.H.)
- Department of Dialysis, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia;
| | - Robert Ekart
- Department of Internal Medicine and Department of Pharmacology, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
- Department of Dialysis, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia;
| | - Radovan Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia; (T.P.); (N.P.); (R.H.)
- Department of Internal Medicine and Department of Pharmacology, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
| | - Sebastjan Bevc
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia; (T.P.); (N.P.); (R.H.)
- Department of Internal Medicine and Department of Pharmacology, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
| |
Collapse
|
|
26
|
Donate-Correa J, Ferri CM, Sánchez-Quintana F, Pérez-Castro A, González-Luis A, Martín-Núñez E, Mora-Fernández C, Navarro-González JF. Inflammatory Cytokines in Diabetic Kidney Disease: Pathophysiologic and Therapeutic Implications. Front Med (Lausanne) 2021; 7:628289. [PMID: 33553221 PMCID: PMC7862763 DOI: 10.3389/fmed.2020.628289] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 12/24/2020] [Indexed: 12/29/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and a main contributing factor for cardiovascular morbidity and mortality in patients with diabetes mellitus. Strategies employed to delay the progression of this pathology focus on the control of traditional risk factors, such as hyperglycemia, and elevated blood pressure. Although the intimate mechanisms involved in the onset and progression of DKD remain incompletely understood, inflammation is currently recognized as one of the main underlying processes. Untangling the mechanisms involved in the appearing of a harmful inflammatory response in the diabetic patient is crucial for the development of new therapeutic strategies. In this review, we focus on the inflammation-related pathogenic mechanisms involved in DKD and in the therapeutic utility of new anti-inflammatory strategies.
Collapse
Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
| | - Carla M. Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Fátima Sánchez-Quintana
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Atteneri Pérez-Castro
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ainhoa González-Luis
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
| |
Collapse
|
|
27
|
Al-Awaida WJ, Hameed WS, Al Hassany HJ, Al-Dabet MM, Al-Bawareed O, Hadi NR. Evaluation of the Genetic Association and Expressions of Notch-2 /Jagged-1 in Patients with Type 2 Diabetes Mellitus. Med Arch 2021; 75:101-108. [PMID: 34219868 PMCID: PMC8228649 DOI: 10.5455/medarh.2021.75.101-108] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background Diabetes mellitus (DM) is the world's most common cause of chronic kidney diseases (CKD), with approximately 1 in 4 adults with DM having CKD and 1 out of 10 to 20% of DM patients die from CKD. Objective The current study aims to investigate the correlation between Notch-2 and Jag-1expressions and specific inflammation biomarkers IL-1β and IL-6 with different stages of diabetic nephropathy. Methods From August 2018 to January 2019, three hundred subjects were recruited for this study. One hundred and fifty subjects were healthy and age-matched to the diabetic group and selected as a control group. Another 150 patients with an established diagnosis of type 2 diabetes (T2DM) according to the criteria of the American Diabetes Association (ADA) were also recruited. Blood specimens were eventually used to identify the expressions Notch-2 and Jagged-1 and the levels of inflammatory biomarkers IL-1β and IL-6. Result The current study shows a significant increase in gene expression and inflammatory biomarkers in patients with moderate and severe diabetic nephropathy compared to the control group. However, there was no significant difference between healthy control and mild diabetic nephropathy patients. This study shows a close association between the increase in the levels of inflammatory biomarkers IL-1β and IL-6 as well as the gene expressions levels of both Notch-2 and Jag-1 with human diabetic nephropathy. Conclusion According to our findings, we emphasize the use of Notch-2 and Jag-1 expressions and IL-1β and IL-6 levels as potential biomarkers for different stages of diabetic nephropathy.
Collapse
Affiliation(s)
- Wajdy J Al-Awaida
- Department of Biology and Biotechnology, American University of Madaba, Madaba, Jordan
| | - Wasan S Hameed
- Department of Microbiology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | - Haider J Al Hassany
- Department of Microbiology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | | | - Omar Al-Bawareed
- Department of normal physiology, RUDN University, Moscow, Russia
| | - Najah R Hadi
- Department of Pharmacology and Therapeutics,Faculty of Medicine, University of Kufa, Kufa, Iraq
| |
Collapse
|
|
28
|
Kong M, Xie K, Lv M, Li J, Yao J, Yan K, Wu X, Xu Y, Ye D. Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: Lessons learned and future promise. Biomed Pharmacother 2021; 133:110975. [PMID: 33212375 DOI: 10.1016/j.biopha.2020.110975] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus (type 1 and type 2) and its various complications continue to place a huge burden on global medical resources, despite the availability of numerous drugs that successfully lower blood glucose levels. The major challenging issue in diabetes management is the prevention of various complications that remain the leading cause of diabetes-related mortality. Moreover, the limited long-term durability of monotherapy and undesirable side effects of currently used anti-diabetic drugs underlie the urgent need for novel therapeutic approaches. Phytochemicals represent a rich source of plant-derived molecules that are of pivotal importance to the identification of compounds with therapeutic potential. In this review, we aim to discuss recent advances in the identification of a large array of phytochemicals with immense potential in the management of diabetes and its complications. Given that metabolic inflammation has been established as a key pathophysiological event that drives the progression of diabetes, we focus on the protective effects of representative phytochemicals in metabolic inflammation. This paper also discusses the potential of phytochemicals in the development of new drugs that target the inflammation in the management of diabetes and its complications.
Collapse
Affiliation(s)
- Mengjie Kong
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Kang Xie
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Minghui Lv
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jufei Li
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jianyu Yao
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Kaixuan Yan
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoqin Wu
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ying Xu
- The First Affiliated Hospital/School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dewei Ye
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
| |
Collapse
|
|
29
|
Liu S, Wang C, Yang H, Zhu T, Jiang H, Chen J. Weighted gene co-expression network analysis identifies FCER1G as a key gene associated with diabetic kidney disease. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1427. [PMID: 33313172 PMCID: PMC7723642 DOI: 10.21037/atm-20-1087] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background Diabetic kidney disease (DKD) is the primary cause of end-stage renal disease. However, the pathogenesis of DKD remains unclarified, and there is an urgent need for improved treatments. Recently, many crucial genes closely linked to the molecular mechanism underlying various diseases were discovered using weighted gene co-expression network analysis. Methods We used a gene expression omnibus series dataset GSE104948 with 12 renal glomerular DKD tissue samples and 18 control samples obtained from the gene expression omnibus database and performed weighted gene co-expression network analysis. After obtaining the trait-related modules, gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses of the modules were conducted and the key gene associated with DKD was selected from the top two most significant gene ontology terms using the maximal clique centrality method. Finally, we verified the key gene using protein-protein interaction analysis, additional datasets, and explored the relationship between the key gene and DKD renal function using the Nephroseq v5 online database. Results Among the 10 gene co-expression modules identified, the darkorange2 and red modules were highly related to DKD and the normal biological process, respectively. Majority of the genes in the darkorange2 module were related to immune and inflammatory responses, and potentially related to the progression of DKD due to their abnormal up-regulation. After performing sub-network analysis of the genes extracted from the top two most significant gene ontology terms and calculating the maximal clique centrality values of each gene, FCER1G, located at the center of the protein-protein interaction network, was identified as a key gene related to DKD. Furthermore, gene expression omnibus validation in additional datasets also showed that FCER1G was overexpressed in DKD compared with normal tissues. Finally, Pearson’s correlation analysis between the expression of FCER1G and DKD renal function revealed that the abnormal upregulation of FCER1G was related to diabetic glomerular lesions. Conclusions Our study demonstrated for the first time that FCER1G is a crucial gene associated with the pathogenesis of DKD.
Collapse
Affiliation(s)
- Shanshan Liu
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Kidney Disease Immunology Laboratory, the Third Grade Laboratory, State Administration of Traditional Chinese Medicine of PR China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.,Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Cuili Wang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Kidney Disease Immunology Laboratory, the Third Grade Laboratory, State Administration of Traditional Chinese Medicine of PR China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.,Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Huiying Yang
- Department of Nephrology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Tingting Zhu
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Kidney Disease Immunology Laboratory, the Third Grade Laboratory, State Administration of Traditional Chinese Medicine of PR China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.,Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Hong Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Kidney Disease Immunology Laboratory, the Third Grade Laboratory, State Administration of Traditional Chinese Medicine of PR China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.,Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Kidney Disease Immunology Laboratory, the Third Grade Laboratory, State Administration of Traditional Chinese Medicine of PR China, Hangzhou, China.,Key Laboratory of Multiple Organ Transplantation, Ministry of Health, Hangzhou, China.,Key Laboratory of Nephropathy, Zhejiang Province, Hangzhou, China.,Institute of Nephropathy, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
30
|
Mitrofanova A, Fontanella AM, Merscher S, Fornoni A. Lipid deposition and metaflammation in diabetic kidney disease. Curr Opin Pharmacol 2020; 55:60-72. [PMID: 33137677 DOI: 10.1016/j.coph.2020.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/16/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022]
Abstract
A critical link between metabolic disorders and a form of low-grade systemic and chronic inflammation has been recently established and named 'Metaflammation'. Metaflammation has been recognized as a key mediator of both microvascular and macrovascular complications of diabetes and as a significant contributor to the development of diabetic kidney disease (DKD). The goal of this review is to summarize the contribution of diabetes-induced inflammation and the related signaling pathways to diabetic complications, with a particular focus on how innate immunity and lipid metabolism influence each other.
Collapse
Affiliation(s)
- Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Antonio M Fontanella
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
| |
Collapse
|
|
31
|
New Insights into the Mechanisms of Pyroptosis and Implications for Diabetic Kidney Disease. Int J Mol Sci 2020; 21:ijms21197057. [PMID: 32992874 PMCID: PMC7583981 DOI: 10.3390/ijms21197057] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/15/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
Pyroptosis is one special type of lytic programmed cell death, featured in cell swelling, rupture, secretion of cell contents and remarkable proinflammation effect. In the process of pyroptosis, danger signalling and cellular events are detected by inflammasome, activating caspases and cleaving Gasdermin D (GSDMD), along with the secretion of IL-18 and IL-1β. Pyroptosis can be divided into canonical pathway and non-canonical pathway, and NLRP3 inflammasome is the most important initiator. Diabetic kidney disease (DKD) is one of the most serious microvascular complications in diabetes. Current evidence reported the stimulatory role of hyperglycaemia-induced cellular stress in renal cell pyroptosis, and different signalling pathways have been shown to regulate pyroptosis initiation. Additionally, the inflammation and cellular injury caused by pyroptosis are tightly implicated in DKD progression, aggravating renal fibrosis, glomerular sclerosis and tubular injury. Some registered hypoglycaemia agents exert suppressive activity in pyroptosis regulation pathway. Latest studies also reported some potential approaches to target the pyroptosis pathway, which effectively inhibits renal cell pyroptosis and alleviates DKD in in vivo or in vitro models. Therefore, comprehensively compiling the information associated with pyroptosis regulation in DKD is the main aim of this review, and we try to provide new insights for researchers to dig out more potential therapies of DKD.
Collapse
|
|
32
|
Role of the Nox4/AMPK/mTOR signaling axe in adipose inflammation-induced kidney injury. Clin Sci (Lond) 2020; 134:403-417. [PMID: 32095833 DOI: 10.1042/cs20190584] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/03/2020] [Accepted: 02/10/2020] [Indexed: 12/25/2022]
Abstract
Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications.
Collapse
|
|
33
|
The Mechanism of Contrast-Induced Acute Kidney Injury and Its Association with Diabetes Mellitus. CONTRAST MEDIA & MOLECULAR IMAGING 2020; 2020:3295176. [PMID: 32788887 PMCID: PMC7330652 DOI: 10.1155/2020/3295176] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 05/26/2020] [Indexed: 02/08/2023]
Abstract
Contrast-induced acute kidney injury (CI-AKI) is the third most common hospital-acquired AKI after AKI induced by renal perfusion insufficiency and nephrotoxic drugs, taking great adverse effects on the prognosis and increasing hospital stay and medical cost. Diabetes nephropathy (DN) is a common chronic complication of DM (diabetes mellitus), and DN is an independent risk factor for chronic kidney disease (CKD) and CI-AKI. The incidence of CI-AKI significantly increases in patients with renal injury, especially in DM-related nephropathy. The etiology of CI-AKI is not fully clear, and research studies on how DM becomes a facilitated factor of CI-AKI are limited. This review describes the mechanism from three aspects. ① Pathophysiological changes of CI-AKI in kidney under high-glucose status (HGS). HGS can enhance the oxidative stress and increase ROS which next causes stronger vessel constriction and insufficient oxygen supply in kidney via vasoactive substances. HGS also aggravates some ion pump load and the latter increases oxygen consumption. CI-AKI and HGS are mutually causal, making the kidney function continue to decline. ② Immunological changes of DM promoting CI-AKI. Some innate immune cells and pattern recognition receptors (PRRs) in DM and/or DN may respond to some damage-associated molecular patterns (DAMPs) formed by CI-AKI. These effects overlap with some pathophysiological changes in hyperglycemia. ③ Signaling pathways related to both CI-AKI and DM. These pathways involved in CI-AKI are closely associated with apoptosis, inflammation, and ROS production, and some studies suggest that these pathways may be potential targets for alleviating CI-AKI. In conclusion, the pathogenesis of CI-AKI and the mechanism of DM as a predisposing factor for CI-AKI, especially signaling pathways, need further investigation to provide new clinical approaches to prevent and treat CI-AKI.
Collapse
|
|
34
|
Abstract
The current unidimensional paradigm of kidney disease detection is incompatible with the complexity and heterogeneity of renal pathology. The diagnosis of kidney disease has largely focused on glomerular filtration, while assessment of kidney tubular health has notably been absent. Following insult, the kidney tubular cells undergo a cascade of cellular responses that result in the production and accumulation of low-molecular-weight proteins in the urine and systemic circulation. Modern advancements in molecular analysis and proteomics have allowed the identification and quantification of these proteins as biomarkers for assessing and characterizing kidney diseases. In this review, we highlight promising biomarkers of kidney tubular health that have strong underpinnings in the pathophysiology of kidney disease. These biomarkers have been applied to various specific clinical settings from the spectrum of acute to chronic kidney diseases, demonstrating the potential to improve patient care.
Collapse
Affiliation(s)
- William R Zhang
- Kidney Health Research Collaborative, University of California San Francisco School of Medicine, San Francisco, California 94121, USA
| | - Chirag R Parikh
- Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA;
| |
Collapse
|
|
35
|
The Interplay of Renin-Angiotensin System and Toll-Like Receptor 4 in the Inflammation of Diabetic Nephropathy. J Immunol Res 2020; 2020:6193407. [PMID: 32411800 PMCID: PMC7210546 DOI: 10.1155/2020/6193407] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/12/2020] [Indexed: 01/11/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most serious chronic kidney diseases and the major cause of end-stage renal failure worldwide. The underlying mechanisms of DN are complex and required to be further investigated. Both innate immunity and renin-angiotensin system (RAS) play critical roles in the pathogenesis of DN. Except for traditional functions, abnormally regulated RAS has been proved to be involved in the inflammatory process of DN. Toll-like receptor 4 (TLR4) is the most deeply studied pattern recognition receptor in the innate immune system, and its activation has been reported to mediate the development of DN. In this review, we aim at discussing how dysregulated RAS affects TLR4 activation in the kidney that contributes to the exploration of the pathogenesis of DN. Understanding the interplay of RAS and TLR4 in inducing the progression of DN may provide new insights to develop effective treatments.
Collapse
|
|
36
|
Macrophage Phenotype and Fibrosis in Diabetic Nephropathy. Int J Mol Sci 2020; 21:ijms21082806. [PMID: 32316547 PMCID: PMC7215738 DOI: 10.3390/ijms21082806] [Citation(s) in RCA: 158] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/11/2020] [Accepted: 04/14/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.
Collapse
|
|
37
|
Leehey DJ. Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline? ACTA ACUST UNITED AC 2020; 1:292-299. [DOI: 10.34067/kid.0001252019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.
Collapse
|
|
38
|
Rashid G, Luzon AA, Korzets Z, Klein O, Zeltzer E, Bernheim J. The Effect of Advanced Glycation End-Products and Aminoguanidine on Tnfα Production by Rat Peritoneal Macrophages. Perit Dial Int 2020. [DOI: 10.1177/089686080102100203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
ObjectiveTo evaluate the effect of advanced glycation end-products (AGEs) and the inhibitor of their formation, aminoguanidine, on tumor necrosis factor-α (TNFα) production (as a functional marker) by rat peritoneal macrophages (PMΦ).DesignCharles River rats underwent a daily intraperitoneal injection of peritoneal dialysis solution [(PDS), 4.25 g/dL dextrose; Dialine, Travenol, Ashdod, Israel] for a 2-month period (group E). Another group of rats was subjected to the same protocol with the addition of 25 mg/kg aminoguanidine (group A). Three control groups were utilized: ( 1 ) rats that were injected daily with aminoguanidine only (group AO), ( 2 ) rats that were injected with Dulbecco's phosphate-buffered saline (group D), and ( 3 ) rats in which no intervention was carried out (group C). After 2 months, PMΦ were isolated from rat peritoneal effluent and their TNFα production measured by ELISA in cell-free culture supernatants, in both the basal state and after 24-hour stimulation with lipopolysaccharide (LPS). The concentrations of AGEs in peritoneal effluent were assayed and correlated to TNFα levels. PMΦ obtained from normal rats were then incubated for 24 hours with ( 1 ) the peritoneal effluent of each of the above respective groups, with or without LPS; ( 2 ) increasing concentrations of AGEs (0 - 250 μg/mL); and ( 3 ) increasing concentrations of aminoguanidine (0 - 7.5 mg/mL), and TNFα secretion again determined.ResultsAfter 2 months of daily intraperitoneal injection of PDS, in the basal state, TNFα production was significantly higher in PMΦ isolated from the peritoneal effluent groups (groups E, A, and AO) compared to controls (group C). Following LPS stimulation, a further increase in TNFα secretion was seen, with a significantly greater response in group AO versus groups E, A, and D. Effluent AGEs were markedly elevated only in group E. No correlation was found between TNFα secretion by these PMΦ and the concentration of AGEs. On incubation with the respective peritoneal effluents (groups E, A, and AO), in both the basal and stimulated state, TNFα production by PMΦ from normal rats was significantly enhanced compared to group C. Incubation with increasing concentrations of AGEs or aminoguanidine resulted in an increase of TNFα secretion by these PMΦ.ConclusionsFollowing intermittent intraperitoneal administration of glucose-based PDS, rat PMΦ are chronically activated, as evidenced by increased basal TNFα secretion. The peritoneal effluent of such treated animals is capable of stimulating TNFα production by normal rat PMΦ. These data suggest that glucose-based PDS acts as a primer of PMΦ, which retain their ability to further stimulation by LPS. Although, in vitro, AGEs promote TNFα secretion by normal rat PMΦ, in vivo, their influence is probably modulated by other factors. Aminoguanidine has a specific inducing effect on rat PMΦ, independent of glucose-based PDS.
Collapse
Affiliation(s)
- Gloria Rashid
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ami-Ad Luzon
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ze'ev Korzets
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Osnat Klein
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ella Zeltzer
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jacques Bernheim
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
39
|
Milas O, Gadalean F, Vlad A, Dumitrascu V, Velciov S, Gluhovschi C, Bob F, Popescu R, Ursoniu S, Jianu DC, Matusz P, Pusztai AM, Secara A, Simulescu A, Stefan M, Patruica M, Petrica F, Vlad D, Petrica L. Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients. J Diabetes Complications 2020; 34:107479. [PMID: 31806428 DOI: 10.1016/j.jdiacomp.2019.107479] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/30/2019] [Accepted: 11/03/2019] [Indexed: 01/18/2023]
Abstract
AIMS To evaluate if there is a link between inflammation (expressed by inflammatory cytokines) and the early stage of diabetic kidney disease (DKD), as shown by markers of podocyte damage and proximal tubular (PT) dysfunction. METHODS In this study were enrolled 117 type 2 DM patients (36-normoalbuminuria, 42-microalbuminuria, 39- macroalbuminuria), and 11 healthy subjects. Serum and urinary IL-1 alpha, IL-8, IL-18, urinary albumin:creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of PT dysfunction (KIM-1, NAG) were assessed. RESULTS In multivariable regression urinary Il-1 alpha correlated positively with podocalyxin and NAG (p < 0.0001, R2= 0.57); urinary IL-8 correlated directly with synaptopodin, NAG, nephrin, and KIM-1 (p < 0.0001, R2 = 0.67); urinary IL-18 correlated directly with synaptopodin, NAG, and nephrin (p < 0.0001, R2 = 0.59). Serum IL-1 alpha correlated positively with nephrin, synaptopodin, NAG (P < 0.0001, R2 = 0.68); serum IL-8 correlated directly with synaptopodin and NAG (p < 0.0001, R2 = 0.66); serum IL-18 correlated directly with NAG, KIM-1, and podocalyxin (p < 0.0001, R2=0.647). CONCLUSIONS Pro-inflammatory interleukins are associated with podocyte injury and PT dysfunction in early DKD. These could exert a key role in the pathogenesis of early DKD, before the development of albuminuria.
Collapse
Affiliation(s)
- Oana Milas
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Florica Gadalean
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania.
| | - Adrian Vlad
- Dept. of Diabetes and Metabolic Diseases, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania.
| | - Victor Dumitrascu
- Dept. of Pharmacology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Silvia Velciov
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Cristina Gluhovschi
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania.
| | - Flaviu Bob
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Roxana Popescu
- Dept. of Cellular and Molecular Biology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Sorin Ursoniu
- Dept. of Public Health Medicine, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; Centre of Translational Research and Systems Medicine, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Dragos Catalin Jianu
- Dept. of Neurology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Petru Matusz
- Dept. of Anatomy and Embryology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania.
| | - Agneta-Maria Pusztai
- Dept. of Anatomy and Embryology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Alina Secara
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Anca Simulescu
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Maria Stefan
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Mihaela Patruica
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Flaviu Petrica
- Nefrotim Medical Center, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Daliborca Vlad
- Dept. of Pharmacology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| | - Ligia Petrica
- Dept. of Nephrology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; Centre of Translational Research and Systems Medicine, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania; "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania
| |
Collapse
|
|
40
|
Lavoz C, Rayego-Mateos S, Orejudo M, Opazo-Ríos L, Marchant V, Marquez-Exposito L, Tejera-Muñoz A, Navarro-González JF, Droguett A, Ortiz A, Egido J, Mezzano S, Rodrigues-Diez RR, Ruiz-Ortega M. Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy? J Clin Med 2020; 9:E272. [PMID: 31963845 PMCID: PMC7019373 DOI: 10.3390/jcm9010272] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/11/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease has become a major medical issue in recent years due to its high prevalence worldwide, its association with premature mortality, and its social and economic implications. A number of patients gradually progress to end-stage renal disease (ESRD), requiring then dialysis and kidney transplantation. Currently, approximately 40% of patients with diabetes develop kidney disease, making it the most prevalent cause of ESRD. Thus, more effective therapies for diabetic nephropathy are needed. In preclinical studies of diabetes, anti-inflammatory therapeutic strategies have been used to protect the kidneys. Recent evidence supports that immune cells play an active role in the pathogenesis of diabetic nephropathy. Th17 immune cells and their effector cytokine IL-17A have recently emerged as promising targets in several clinical conditions, including renal diseases. Here, we review current knowledge regarding the involvement of Th17/IL-17A in the genesis of diabetic renal injury, as well as the rationale behind targeting IL-17A as an additional therapy in patients with diabetic nephropathy.
Collapse
Affiliation(s)
- Carolina Lavoz
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
| | - Sandra Rayego-Mateos
- Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198 Lleida, Spain;
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
| | - Macarena Orejudo
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Lucas Opazo-Ríos
- Renal, Vascular and Diabetes Research Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.O.-R.); (J.E.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Vanessa Marchant
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Laura Marquez-Exposito
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Antonio Tejera-Muñoz
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación y Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
| | - Alejandra Droguett
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
| | - Alberto Ortiz
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Nephrology and Hypertension, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.O.-R.); (J.E.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Sergio Mezzano
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
| | - Raúl R. Rodrigues-Diez
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Marta Ruiz-Ortega
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| |
Collapse
|
|
41
|
Zheng YH, Ren CY, Shen Y, Li JB, Chen MW. A Cross-Sectional Study on the Correlation Between Inflammatory Cytokines, Negative Emotions, and Onset of Peripheral Neuropathy in Type 2 Diabetes. Neuropsychiatr Dis Treat 2020; 16:2881-2890. [PMID: 33293813 PMCID: PMC7718991 DOI: 10.2147/ndt.s278439] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 11/09/2020] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE This study explored the changes in the levels of IL-6, IL-17, TNF-α, and TNF-β, whether such changes were associated with anxiety and depression in diabetic peripheral neuropathy (DPN), and what factors associated with the occurrence of DPN. METHODS Forty-four patients diagnosed with DPN comprised the DPN group, including DPN1 (mild diabetic peripheral neuropathy, 29 cases) and DPN2 groups (moderate-severe diabetic peripheral neuropathy, 15 cases). Thirty-seven individuals with type 2 diabetes mellitus constituted the diabetes mellitus with no neuropathy (NDPN) group. Electromyography was applied to confirm DPN, and the Toronto clinical scoring system (TCSS) score was used to assess the severity of DPN. All subjects' emotions were evaluated using the self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Triiodothyronine (T3), tetraiodothyronine (T4), and thyroid-stimulating hormone (TSH) levels were measured using chemiluminescent immunoassay. The relevant biochemical indicators were detected using an automatic biochemical analyzer. The plasma levels of cytokines were detected using quantitative sandwich enzyme-linked immunosorbent assay. RESULTS Patients with DPN had elevated levels of anxiety, IL-6, IL-17, and TNF-α. There were some positive associations between negative emotions and cytokines. The TCSS score positively correlated with IL-17, SAS score, and T3. DPN independently correlated with age, disease duration, fasting plasma glucose (FPG), and IL-17. The combination of IL-17 and TNF-α had higher diagnostic value for DPN than any single cytokine. CONCLUSION Patients with DPN had elevated levels of inflammatory cytokines, which were associated with negative emotion, and IL-17 had independent correlation with DPN.
Collapse
Affiliation(s)
- Ya-Hong Zheng
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Chong-Yang Ren
- Department of Neurology (Sleep Disorder), The Affiliated Chaohu Hospital of Anhui Medical University, Chaohu 238000, People's Republic of China
| | - Ying Shen
- Department of Endocrinology, Nanjing Tongren Hospital, Nanjing 211102, People's Republic of China
| | - Jia-Bin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China.,Department of Infectious Diseases, The Affiliated Chaohu Hospital of Anhui Medical University, Chaohu 238000, People's Republic of China.,Anhui Center for Surveillance of Bacterial Resistance, Hefei 230022, People's Republic of China.,Institute of Bacterial Resistance, Anhui Medical University, Hefei 230022, People's Republic of China
| | - Ming-Wei Chen
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| |
Collapse
|
|
42
|
Inflammation and Oxidative Stress in Chronic Kidney Disease-Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites. Int J Mol Sci 2019; 21:ijms21010263. [PMID: 31906008 PMCID: PMC6981831 DOI: 10.3390/ijms21010263] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/23/2019] [Accepted: 12/27/2019] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.
Collapse
|
|
43
|
Vallon V, Unwin R, Inscho EW, Leipziger J, Kishore BK. Extracellular Nucleotides and P2 Receptors in Renal Function. Physiol Rev 2019; 100:211-269. [PMID: 31437091 DOI: 10.1152/physrev.00038.2018] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This review attempts to integrate the available data while also identifying areas of missing information. First, the determinants of nucleotide concentrations in the interstitial and tubular fluids of the kidney are described, including mechanisms of cellular release of nucleotides and their extracellular breakdown. Then the renal cell membrane expression of P2X and P2Y receptors is discussed in the context of their effects on renal vascular and tubular functions. Attention is paid to effects on the cortical vasculature and intraglomerular structures, autoregulation of renal blood flow, tubuloglomerular feedback, and the control of medullary blood flow. The role of the nucleotide/P2 receptor system in the autocrine/paracrine regulation of sodium and fluid transport in the tubular and collecting duct system is outlined together with its role in integrative sodium and fluid homeostasis and blood pressure control. The final section summarizes the rapidly growing evidence indicating a prominent role of the extracellular nucleotide/P2 receptor system in the pathophysiology of the kidney and aims to identify potential therapeutic opportunities, including hypertension, lithium-induced nephropathy, polycystic kidney disease, and kidney inflammation. We are only beginning to unravel the distinct physiological and pathophysiological influences of the extracellular nucleotide/P2 receptor system and the associated therapeutic perspectives.
Collapse
Affiliation(s)
- Volker Vallon
- Departments of Medicine and Pharmacology, University of California San Diego & VA San Diego Healthcare System, San Diego, California; Centre for Nephrology, Division of Medicine, University College London, London, United Kingdom; IMED ECD CVRM R&D, AstraZeneca, Gothenburg, Sweden; Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Biomedicine/Physiology, Aarhus University, Aarhus, Denmark; Departments of Internal Medicine and Nutrition and Integrative Physiology, and Center on Aging, University of Utah Health & Nephrology Research, VA Salt Lake City Healthcare System, Salt Lake City, Utah
| | - Robert Unwin
- Departments of Medicine and Pharmacology, University of California San Diego & VA San Diego Healthcare System, San Diego, California; Centre for Nephrology, Division of Medicine, University College London, London, United Kingdom; IMED ECD CVRM R&D, AstraZeneca, Gothenburg, Sweden; Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Biomedicine/Physiology, Aarhus University, Aarhus, Denmark; Departments of Internal Medicine and Nutrition and Integrative Physiology, and Center on Aging, University of Utah Health & Nephrology Research, VA Salt Lake City Healthcare System, Salt Lake City, Utah
| | - Edward W Inscho
- Departments of Medicine and Pharmacology, University of California San Diego & VA San Diego Healthcare System, San Diego, California; Centre for Nephrology, Division of Medicine, University College London, London, United Kingdom; IMED ECD CVRM R&D, AstraZeneca, Gothenburg, Sweden; Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Biomedicine/Physiology, Aarhus University, Aarhus, Denmark; Departments of Internal Medicine and Nutrition and Integrative Physiology, and Center on Aging, University of Utah Health & Nephrology Research, VA Salt Lake City Healthcare System, Salt Lake City, Utah
| | - Jens Leipziger
- Departments of Medicine and Pharmacology, University of California San Diego & VA San Diego Healthcare System, San Diego, California; Centre for Nephrology, Division of Medicine, University College London, London, United Kingdom; IMED ECD CVRM R&D, AstraZeneca, Gothenburg, Sweden; Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Biomedicine/Physiology, Aarhus University, Aarhus, Denmark; Departments of Internal Medicine and Nutrition and Integrative Physiology, and Center on Aging, University of Utah Health & Nephrology Research, VA Salt Lake City Healthcare System, Salt Lake City, Utah
| | - Bellamkonda K Kishore
- Departments of Medicine and Pharmacology, University of California San Diego & VA San Diego Healthcare System, San Diego, California; Centre for Nephrology, Division of Medicine, University College London, London, United Kingdom; IMED ECD CVRM R&D, AstraZeneca, Gothenburg, Sweden; Department of Medicine, Division of Nephrology, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Biomedicine/Physiology, Aarhus University, Aarhus, Denmark; Departments of Internal Medicine and Nutrition and Integrative Physiology, and Center on Aging, University of Utah Health & Nephrology Research, VA Salt Lake City Healthcare System, Salt Lake City, Utah
| |
Collapse
|
|
44
|
Rehman MU, Rashid SM, Rasool S, Shakeel S, Ahmad B, Ahmad SB, Madkhali H, Ganaie MA, Majid S, Bhat SA. Zingerone (4-(4-hydroxy-3-methylphenyl)butan-2-one) ameliorates renal function via controlling oxidative burst and inflammation in experimental diabetic nephropathy. Arch Physiol Biochem 2019. [PMID: 29537332 DOI: 10.1080/13813455.2018.1448422] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Development of diabetic nephropathy (DN) is directly linked to oxidative stress and inflammation. In this context, inflammatory and oxidative markers have gained much attention as targets for therapeutic intervention. We studied the effect of zingerone in a streptozotocin/high fat diet (STZ/HFD)-induced type 2 diabetic Wistar rat model. Zingerone also known as vanillyl acetone is a pharmacologically active compound present usually in dry ginger. STZ/HFD caused excessive increase in ROS and inflammation in experimental animals. The treatment with zingerone markedly abrogated ROS levels, inhibited the NF-кB activation and considerably reduced level of other downstream inflammatory molecules (TNF-α, IL-6, IL-1β), furthermore, zingerone treatment improved renal functioning by significantly decreasing the levels of kidney toxicity markers KIM-1, BUN, creatinine, and LDH and suppressed TGF-β. Collectively, these findings indicate that zingerone treatment improved renal function by anti-hyperglycaemic, anti-oxidant, and anti-inflammatory effects, suggesting the efficacy of zingerone in the treatment of DN.
Collapse
Affiliation(s)
- Muneeb U Rehman
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Shahzada Mudasir Rashid
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Saiema Rasool
- b Department of Forest ManagementForest Biotech Lab , Universiti Putra Malaysia , Serdang , Malaysia
| | - Sheeba Shakeel
- c Department of Pharmaceutical Sciences , University of Kashmir , Srinagar , India
| | - Bilal Ahmad
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Sheikh Bilal Ahmad
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Hassan Madkhali
- d Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Kingdom of Saudi Arabia
| | - Majid Ahmad Ganaie
- d Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Kingdom of Saudi Arabia
| | - Sabiya Majid
- e Department of Biochemistry , Govt. Medical College , Srinagar , India
| | | |
Collapse
|
|
45
|
Donate-Correa J, Tagua VG, Ferri C, Martín-Núñez E, Hernández-Carballo C, Ureña-Torres P, Ruiz-Ortega M, Ortiz A, Mora-Fernández C, Navarro-González JF. Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons. J Clin Med 2019; 8:287. [PMID: 30818852 PMCID: PMC6463074 DOI: 10.3390/jcm8030287] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/21/2019] [Accepted: 02/22/2019] [Indexed: 12/26/2022] Open
Abstract
Diabetic kidney disease is one of the most relevant complications in diabetes mellitus patients, which constitutes the main cause of end-stage renal disease in the western world. Delaying the progression of this pathology requires new strategies that, in addition to the control of traditional risk factors (glycemia and blood pressure), specifically target the primary pathogenic mechanisms. Nowadays, inflammation is recognized as a critical novel pathogenic factor in the development and progression of renal injury in diabetes mellitus. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic properties clinically used for more than 30 years in the treatment of peripheral vascular disease. In addition, this compound also exerts anti-inflammatory actions. In the context of diabetic kidney disease, pentoxifylline has shown significant antiproteinuric effects and a delay in the loss of estimated glomerular filtration rate, although at the present time there is no definitive evidence regarding renal outcomes. Moreover, recent studies have reported that this drug can be associated with a positive impact on new factors related to kidney health, such as Klotho. The use of pentoxifylline as renoprotective therapy for patients with diabetic kidney disease represents a new example of drug repositioning.
Collapse
Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain.
| | - Víctor G Tagua
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
| | - Carla Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain.
| | | | - Pablo Ureña-Torres
- Department of Dialyisis, AURA Nord, Saint Ouen, 93400 Paris, France.
- Department of Renal Physiology, Necker Hospital, University Paris Descartes, 75006 Paris, France.
| | - Marta Ruiz-Ortega
- Laboratorio de Biología Celular en Enfermedades Renales, Universidad Autónoma Madrid, IIS-Fundación Jiménez Díaz, Madrid, 28004, Spain.
- REDINREN (Red de Investigación Renal-RD16/0009/0007), Instituto de Salud Carlos III, Madrid, 28029, Spain.
| | - Alberto Ortiz
- Departamento de Nefrología e Hipertensión, IIS-Fundación Jiménez Díaz y Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
- REDINREN (Red de Investigación Renal-RD16/0009/0001), Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain.
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Juan F Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain.
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain.
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38010 Santa Cruz de Tenerife, Spain.
| |
Collapse
|
|
46
|
Cho EH, Kim SW. Soluble Dipeptidyl Peptidase-4 Levels Are Associated with Decreased Renal Function in Patients with Type 2 Diabetes Mellitus. Diabetes Metab J 2019; 43:97-104. [PMID: 30302966 PMCID: PMC6387880 DOI: 10.4093/dmj.2018.0030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/16/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Dipeptidyl peptidase-4 (DPP-4) is strongly expressed in the kidney, and soluble levels of this protein are used as a marker in various chronic inflammatory diseases, including diabetes, coronary artery disease, and cancer. This study examined the association between the serum soluble DPP-4 levels and renal function or cardiovascular risk in patients with type 2 diabetes mellitus. METHODS In this retrospective analysis, soluble DPP-4 levels were measured in preserved sera from 140 patients with type 2 diabetes mellitus who had participated in our previous coronary artery calcium (CAC) score study. RESULTS The mean±standard deviation soluble DPP-4 levels in our study sample were 645±152 ng/mL. Univariate analyses revealed significant correlations of soluble DPP-4 levels with the total cholesterol (r=0.214, P=0.019) and serum creatinine levels (r=-0.315, P<0.001) and the estimated glomerular filtration rate (eGFR; estimated using the modification of diet in renal disease equation) (r=0.303, P=0.001). The associations of soluble DPP-4 levels with serum creatinine and GFR remained significant after adjusting for age, body mass index, and duration of diabetes. However, no associations were observed between soluble DPP-4 levels and the body mass index, waist circumference, or CAC score. CONCLUSION These data suggest the potential use of serum soluble DPP-4 levels as a future biomarker of deteriorated renal function in patients with type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Eun Hee Cho
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Sang Wook Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea.
| |
Collapse
|
|
47
|
Esfandiari A, Pourghassem Gargari B, Noshad H, Sarbakhsh P, Mobasseri M, Barzegari M, Arzhang P. The effects of vitamin D 3 supplementation on some metabolic and inflammatory markers in diabetic nephropathy patients with marginal status of vitamin D: A randomized double blind placebo controlled clinical trial. Diabetes Metab Syndr 2019; 13:278-283. [PMID: 30641712 DOI: 10.1016/j.dsx.2018.09.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 09/11/2018] [Indexed: 11/17/2022]
Abstract
AIMS Diabetic nephropathy is known to be an independent risk factor in the progression of renal and cardiovascular disorders. Due to the association between vitamin D deficiency and diabetic nephropathy, vitamin D deficiency in the diabetic nephropathy population, this study conducted to examine the effects of Vitamin D3 on metabolic and inflammatory parameters in patients with diabetic nephropathy. METHODS This eight-week, randomized, double-blind, placebo-controlled trial was carried out on 50 diabetic nephropathy patients with marginal status of vitamin D. Participants were randomly assigned to two groups: control and intervention. Participants received a vitamin D3 (50000 IU) supplement weekly on a specific day. Fasting blood samples were collected from all patients at their entry to the study, and eight weeks after intervention. RESULTS Analyses showed significance differences in physical activity between the intervention and placebo groups (P = 0.018). There were no significant differences between the percentage changes of HbA1c, insulin and, inflammatory parameters such as TNF-α and IL-6 (P > 0.05), while the percentage change of FBS was significantly higher in the placebo group compared to the treatment one (P < 0.0001). Lower levels of FBS (P < 0.0001), insulin (P < 0.069), HOMA-IR (P < 0.001), TNF-α (P< 0.002) and IL-6 (P < 0.037) were found after supplementation in treatment group. However, the phosphorous and protein percentage change in urine were lower (P = 0.07) and higher (P = 0.003) between groups. CONCLUSIONS It was found that vitamin D supplementation can be regarded as an effective way to prevent the progression of diabetic nephropathy by reducing levels of proteinuria, and inflammatory markers such as TNF-α and IL-6.
Collapse
Affiliation(s)
- A Esfandiari
- School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - B Pourghassem Gargari
- Nutrition Research Center, Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.
| | - H Noshad
- Chronic Kidney Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - P Sarbakhsh
- Department of Statistics and Epidemiology, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - M Mobasseri
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disorders, Imam Reza Teaching Hospital, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - M Barzegari
- School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - P Arzhang
- School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| |
Collapse
|
|
48
|
Yaribeygi H, Katsiki N, Butler AE, Sahebkar A. Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys. Drug Discov Today 2019; 24:256-262. [DOI: 10.1016/j.drudis.2018.08.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/30/2018] [Accepted: 08/01/2018] [Indexed: 12/18/2022]
|
|
49
|
Wang J, Yan W, Peng X, Jiang Y, He L, Peng Y, Chen X, Ye M, Zhuo H. Functional Role of SUV39H1 in Human Renal Tubular Epithelial Cells Under High-glucose Ambiance. Inflammation 2018; 41:1-10. [PMID: 28852907 DOI: 10.1007/s10753-017-0657-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
SUV39H1, the histone methyltransferase (HMTase) of histone H3 lysine 9 trimethylation (H3K9me3), is a known transcriptional repressor of inflammatory genes. The effect of SUV39H1 on inflammatory gene promoters under high-glucose stimulation in vascular smooth muscle cells (VSMCs), macrophages, and cardiomyocytes has been studied, but how SUV39H1 functions in renal tubules under diabetic conditions is unclear. Renal biopsy specimens of ten diabetic nephropathy (DN) subjects and seven non-DN minimal change diseases (MCD) subjects were collected. SUV39H1, IL-6, and MCP-1 expression in renal tissues were measured using immunohistochemical, while SUV39H1, H3K9me3, IL-6, and MCP-1 in human proximal tubular epithelial cells (HK-2) under varying glucose conditions were assayed by Western blot and ELISA. SUV39H1 was overexpressed in HK-2 cells; the regulation of SUV39H1 and H3K9me3 on NF-κB, IL-6, MCP-1, caspase 3, and apoptosis was measured. SUV39H1 was expressed more in diabetic human renal tubules. HK-2 cells with high glucose up-regulated IL-6 and MCP-1 in a dose- and time-dependent manner, and SUV39H1 expression was reduced with greater glucose and prolonged stimulation. Expression of H3K9me3 was synchronized with SUV39H1. Moreover, overexpression of SUV39H1 in high glucose environment was accompanied with increased H3K9me3 and decreased inflammation and apoptosis. SUV39H1 dysregulation may be involved in DN progression. Overexpression of SUV39H1 may reduce renal inflammation and apoptosis via epigenetic modulation, thus plays a protective role in DN.
Collapse
Affiliation(s)
- Jiayi Wang
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Wenzhe Yan
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Xiaofei Peng
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Yafeng Jiang
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Liyu He
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Youming Peng
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China.
| | - Xian Chen
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Muyao Ye
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Hui Zhuo
- Nephrology Department, Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| |
Collapse
|
|
50
|
Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 2018; 107:306-328. [PMID: 30098549 DOI: 10.1016/j.biopha.2018.07.157] [Citation(s) in RCA: 267] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/15/2018] [Accepted: 07/31/2018] [Indexed: 02/09/2023] Open
Abstract
Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic β-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia.
Collapse
Affiliation(s)
- Biplab Giri
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India.
| | - Sananda Dey
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Tanaya Das
- Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Mrinmoy Sarkar
- Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Jhimli Banerjee
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India
| | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India.
| |
Collapse
|