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Zhang H, Jiang Y, Song J, Wang S, Lu J, Wei F, Li X. Urinary exosomes exacerbate diabetic kidney disease by promoting NLRP3 inflammasome activation via the microRNA-516b-5p/SIRT3/AMPK pathway. Am J Physiol Endocrinol Metab 2025; 328:E911-E923. [PMID: 40337989 DOI: 10.1152/ajpendo.00527.2024] [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: 01/07/2025] [Revised: 02/10/2025] [Accepted: 04/29/2025] [Indexed: 05/09/2025]
Abstract
Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus. Urinary exosomal miRNAs play a prominent regulatory role in the pathogenesis of DKD, but the potential mechanisms remain largely unknown. Our research was designed to explain the pathogenesis of urine-derived exosomal microRNA-516b-5p (miR-516b-5p) in the DKD development. Urine-derived exosomes were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Immunofluorescence staining was used to detect cellular internalization. Quantitative real time-polymerase chain reaction (qRT-PCR) analysis was performed to measure the levels of miR-516b-5p and SIRT3. The secretion of inflammatory cytokines and Caspase-1 activity were evaluated via ELISA and flow cytometry, respectively. Expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome markers and genes associated with the SIRT3/AMPK signaling pathway were measured using Western blot. Bioinformatics tools and dual-luciferase reporter gene assay were used to confirm the correlation between miR-516b-5p and SIRT3. Blood glucose and renal function indexes were determined by the corresponding commercial kits. Hematoxylin and eosin (H&E) staining was exploited to examine the renal pathological changes. MiR-516b-5p was memorably upregulated in HKB-20 cells exposed to DKD-Exo. DKD-Exo introduction led to an increase in Caspase-1 activity, promoted inflammatory response and NLRP3 inflammasome activity, and inactivation of SIRT3/AMPK signaling pathway, which was partially reversed by silencing miR-516b-5p. SIRT3 was identified as a target gene of miR-516b-5p. SIRT3 overexpression reversed the influences of DKD-Exo and miR-516b-5p mimic. In the in vivo model, DKD-Exo exacerbated streptozotocin (STZ)-induced kidney injury through promoting inflammatory response and activating the NLRP3 inflammasome. Urinary exosomal miR-516b-5p plays a key role in DKD by promoting inflammatory response and activating the NLRP3 inflammasome through the SIRT3/AMPK pathway.NEW & NOTEWORTHY Urinary exosomal miR-516b-5p plays a key role in diabetic kidney disease (DKD) by promoting inflammatory response and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation through the SIRT3/AMPK pathway.
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Affiliation(s)
- Haiying Zhang
- Department of Endocrine Metabolism, The Third Affiliated Hospital of Chengdu Medical College, Chengdu Pidu District People's Hospital, Chengdu, People's Republic of China
| | - Yubo Jiang
- Department of Nephrology, The Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital, Chengdu, People's Republic of China
| | - Jun Song
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Traditional Chinese Medicine of Chengdu Medical College, XinDu District Hospital of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Shaoqing Wang
- Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People's Republic of China
| | - Jianhong Lu
- Department of Clinical Medicine, School of Clinical Medicine, Chengdu Medical College, Chengdu, People's Republic of China
| | - Fuxin Wei
- Department of Clinical Medicine, School of Clinical Medicine, Chengdu Medical College, Chengdu, People's Republic of China
| | - Xiu Li
- School of Basic Medical Sciences, Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, People's Republic of China
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Yang M, Luo S, Yang J, Chen W, He L, Liu D, Wang X, Xiao L, Sun L. DsbA-L: A Promising Therapeutic Target for Metabolic Diseases. Curr Med Chem 2025; 32:982-991. [PMID: 37877503 DOI: 10.2174/0109298673252630231018044159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/20/2023] [Accepted: 09/15/2023] [Indexed: 10/26/2023]
Abstract
The increasing incidence of metabolic diseases, including obesity and diabetes, is a serious social public problem. Therefore, there is an urgent need to find effective prevention and treatment measures for these diseases. DsbA-L is a protein that is widely expressed in many tissues and is closely related to metabolism. Emerging evidence shows that DsbA-L plays an important role in antioxidative stress, promoting the synthesis and secretion of adiponectin and maintaining mitochondrial homeostasis, and the abnormalities of these functions are also closely related to the occurrence and development of metabolic diseases. Here, we reviewed the tissue expression patterns and regulatory factors of DsbA-L, summarized its biological functions and the current research progress of DsbA-L in metabolic diseases, and found that DsbA-L may be a promising target for metabolic diseases.
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Affiliation(s)
- Ming Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Di Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xi Wang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Xiao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
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Li S, Wan J, Peng Z, Huang Q, He B. New insights of DsbA-L in the pathogenesis of metabolic diseases. Mol Cell Biochem 2024; 479:3293-3303. [PMID: 38430301 DOI: 10.1007/s11010-024-04964-8] [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: 11/29/2023] [Accepted: 02/10/2024] [Indexed: 03/03/2024]
Abstract
Metabolic diseases, such as obesity, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD), are abnormal conditions that result from disturbances of metabolism. With the improvement of living conditions, the morbidity and mortality rates of metabolic diseases are steadily rising, posing a significant threat to human health worldwide. Therefore, identifying novel effective targets for metabolic diseases is crucial. Accumulating evidence has indicated that disulfide bond A oxidoreductase-like protein (DsbA-L) delays the development of metabolic diseases. However, the underlying mechanisms of DsbA-L in metabolic diseases remain unclear. In this review, we will discuss the roles of DsbA-L in the pathogenesis of metabolic diseases, including obesity, diabetes mellitus, and NAFLD, and highlight the potential mechanisms. These findings suggest that DsbA-L might provide a novel therapeutic strategy for metabolic diseases.
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Affiliation(s)
- Siqi Li
- Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jinfa Wan
- Department of Emergency Medicine, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Zhenyu Peng
- Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Emergency Medicine and Difficult Diseases Institute, Central South University, Changsha, 410011, China
| | - Qiong Huang
- Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Baimei He
- Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Wang J, Xia Z, Qing B, Chen Y, Gu L, Chen H, Ge Z, Yuan Y. DsbA-L activates TGF-β1/SMAD3 signaling and M2 macrophage polarization by stimulating AKT1 and NLRP3 to promote pulmonary fibrosis. Mol Med 2024; 30:228. [PMID: 39580448 PMCID: PMC11585156 DOI: 10.1186/s10020-024-00983-9] [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: 06/12/2024] [Accepted: 11/01/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a progressive and difficult-to-heal lung disease that poses a significant threat to human life and health. This study aimed to investigate the potential pathological mechanisms of PF and to identify new avenues for the treatment of PF. METHODS Clinical samples were collected to assess the effect of disulfide-bond A oxidoreductase-like protein (DsbA-L) on PF. TGF-β1-induced MLE-12 cell model and bleomycin (BLM)-induced mice model were established. Changes in physiological morphology and fibrosis were observed in the lung tissues. The degree of apoptosis and the mitochondrial function was analyzed. The expression of relative cytokines was examined. The CD68+/CD206+ ratio was determined to indicate M2 macrophage polarization. RESULTS The expression of DsbA-L was upregulated in patients with PF and PF-like models. In vitro, DsbA-L overexpression exacerbated TGF-β1-induced the deposition of extracellular matrix (ECM), apoptosis, inflammation, and mitochondrial damage, whereas DsbA-L silencing exerted the opposite effects. DsbA-L silencing inhibited the activation of AKT1, NLRP3, and SMAD3 by TGF-β1. MLE-12 cells silencing DsbA-L limited the polarization of RAW264.7 cells towards the M2 phenotype. AKT1 agonist or NLRP3 agonist reversed the role of DsbA-L silencing in inhibiting the TGF-β1/SMAD3 pathway and M2 macrophage polarization. In vivo, DsbA-L knockout protected mice from PF-like pathological damage caused by BLM. CONCLUSION DsbA-L exhibited a significant profibrotic effect in lung epithelial cells and mice, which increased the levels of AKT1 and NLRP3 to activate the TGF-β1/SMAD3 pathway and M2 macrophage polarization. These findings could shed light on new clues for comprehension and treatment of PF.
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Affiliation(s)
- Juan Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhenkun Xia
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Bei Qing
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ying Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Linguo Gu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hongzuo Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhenglian Ge
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yunchang Yuan
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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Li X, Liu S, Huangfu J, Lai N, Shang Y. Clinical significance of NLRP3 inflammasome and related cell molecules in early diabetic kidney disease in elderly population. J Med Biochem 2024; 43:828-834. [PMID: 39876912 PMCID: PMC11771978 DOI: 10.5937/jomb0-45950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/23/2024] [Indexed: 01/31/2025] Open
Abstract
Background The paper aims to investigate the expression level of NLRP3 inflammasome and its related cell molecules in early diabetes kidney disease (EDKD) in the elderly and its clinical application value. Methods From October 2021 to April 2023, 50 elderly patients with T2DM (T2DM group), 50 elderly patients with EDKD (EDKD group) and 50 elderly people who passed the health check-up (healthy group) were chosen as the study subjects. Plasma NLRP3 inflammasome and related cells (blood leukocyte count, monocyte count, lymphocyte count) molecular (NT-proBNP and others) levels are tested, and Pearson correlation analysis is utilized to explore the correlation among plasma NLRP3 inflammasome and related cells, molecules, and renal function indicators (UACR, BUN, Ucr) in elderly patients with EDKD. Results (1) The three groups' comparison in HbA1c, FIns, HOMA-IR, UACR, BUN, Ucr, SOD, MCP-1, and TNF-a levels were with P<0.05. The levels of TG and LDL-C in the EDKD group were higher than those in the T2DM and the healthy groups; the levels of FPG, HbA1c, FINs, HOMA-IR, UACR, SOD, MCP-1, TNF-a in the EDKD and T2DM groups were higher than those in the healthy group, while SOD was smaller than that in the healthy group; the levels of BUN, Ucr, hs-CRP, FPG, HbA1c, FINs, HOMA-IR, UACR, SOD, MCP-1, TNF-a in the EDKD group were higher than those in the T2DM group, while SOD was smaller than that in the T2DM group. The above results were with P<0.05. (2) It has P<0.05 in Monocyte count, NLRP3, NT-proBNP, caspase-1, ASC and others in the three groups. Those in the EDKD and T2DM groups were higher than those in the healthy group. The levels of these indicators in the EDKD group were higher than those in the T2DM group, with P<0.05. NLRP3, Caspase-1, ASC, IL1b, and IL-18 were positively correlated with UACR, BUN, and Ucr in the EDKD group. All the above differences were P<0.05. Conclusions NLRP3 inflammasome and its related molecules caspase-1, ASC, IL-1b, IL-18 and other levels increase in early elderly EDKD and are closely related to the severity of EDKD.
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Affiliation(s)
- Xiaoli Li
- Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Department of Endocrinology, Taiyuan, China
| | - Shiwei Liu
- Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Department of Endocrinology, Taiyuan, China
| | - Jinrong Huangfu
- Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Department of Endocrinology, Taiyuan, China
| | - Nannan Lai
- Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Department of Endocrinology, Taiyuan, China
| | - Yan Shang
- Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Department of Nephrology, Taiyuan, China
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Fan MW, Tian JL, Chen T, Zhang C, Liu XR, Zhao ZJ, Zhang SH, Chen Y. Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications. World J Diabetes 2024; 15:2041-2057. [PMID: 39493568 PMCID: PMC11525733 DOI: 10.4239/wjd.v15.i10.2041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 08/14/2024] [Accepted: 08/26/2024] [Indexed: 09/26/2024] Open
Abstract
Diabetes mellitus (DM) is one of the major causes of mortality worldwide, with inflammation being an important factor in its onset and development. This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway in mediating inflammatory responses. Furthermore, it comprehensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM, diabetic gastroenteropathy, diabetic cardiomyopathy, non-alcoholic fatty liver disease, and other complications. Additionally, the role of cGAS-STING in autonomic dysfunction and intestinal dysregulation, which can lead to digestive complications, has been discussed. Altogether, this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.
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Affiliation(s)
- Ming-Wei Fan
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Jin-Lan Tian
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Tan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Can Zhang
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Xin-Ru Liu
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Zi-Jian Zhao
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Shu-Hui Zhang
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
| | - Yan Chen
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
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Wu Y, Xu Y, Deng H, Sun J, Li X, Tang J. Poricoic acid a ameliorates high glucose-induced podocyte injury by regulating the AMPKα/FUNDC1 pathway. Mol Biol Rep 2024; 51:1003. [PMID: 39305364 DOI: 10.1007/s11033-024-09921-8] [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: 05/23/2024] [Accepted: 09/05/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Poricoic acid A (PAA), a major triterpenoid component of Poria cocos with anti-tumor, anti-fibrotic, anti-inflammatory, and immune-regulating activities, has been shown to induce podocyte autophagy in diabetic kidney disease (DKD) by downregulating FUN14 domain containing 1 (FUNDC1). This study aimed to identify the role of adenosine monophosphate-activated protein kinase alpha (AMPKα) in PAA-mediated phosphorylation of FUNDC1 in podocyte injury occurring in the pathogenesis of DKD. METHODS AND RESULTS A cellular model of renal podocyte injury was established by culturing MPC5 cells under high-glucose (HG) conditions. MPC5 cells were subjected to transfection with small interfering RNA (siRNA) targeting AMPKα or siRNA targeting FUNDC1, an AMPKα activator, or PAA. PAA treatment induced the phosphorylation of AMPKα in HG-cultured podocytes. AMPKα activation was implicated in the inhibitory effect of PAA on FUNDC phosphorylation in HG-cultured podocytes. Treatment targeting the AMPKα activator also significantly augmented proliferation, migration, mitochondrial membrane potential, and autophagy levels, while reducing apoptosis levels, inhibiting oxidative stress, and suppressing the release of proinflammatory factors in HG-cultured MPC5 cells. In contrast, insufficient expression of AMPKα reversed the effects of PAA on the proliferation, migration, and apoptosis of podocytes and further exacerbated the reduction of phosphorylated FUNDC1 expression in podocytes under HG conditions. CONCLUSIONS AMPKα is involved in the regulation of FUNDC1 phosphorylation by PAA in HG-induced podocyte injury. Furthermore, the AMPKα/FUNDC1 pathway plays a crucial regulatory role in HG-induced podocyte injury. These findings support AMPKα, FUNDC1, and the AMPKα/FUNDC1 pathway as targets for PAA intervention.
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Affiliation(s)
- Yuwen Wu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China.
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China
| | - Haohua Deng
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China
| | - Jiazhong Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China
| | - Xin Li
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China
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Sun T, Guo Y, Su Y, Shan S, Qian W, Zhang F, Li M, Zhang Z. Molecular mechanisms of diabetic nephropathy: A narrative review. Cell Biol Int 2024; 48:1240-1253. [PMID: 38946126 DOI: 10.1002/cbin.12212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/01/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024]
Abstract
Diabetic nephropathy (DN) is the predominant secondary nephropathy resulting in global end-stage renal disease. It is attracting significant attention in both domestic and international research due to its widespread occurrence, fast advancement, and limited choices for prevention and treatment. The pathophysiology of this condition is intricate and involves multiple molecular and cellular pathways at various levels. This article provides a concise overview of the molecular processes involved in the development of DN. It discusses various factors, such as signaling pathways, cytokines, inflammatory responses, oxidative stress, cellular damage, autophagy, and epigenetics. The aim is to offer clinicians a valuable reference for DN's diagnosis, treatment, and intervention.
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Affiliation(s)
- Tian Sun
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yina Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yanting Su
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Shigang Shan
- School of Public Health and Nursing, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Wenbin Qian
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Feixue Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Mengxi Li
- School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and Technology, Xianning, China
| | - Zhenwang Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
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Yang M, Liu Y, Luo SL, Liu CB, Jiang N, Li CR, Zhao H, Han YC, Chen W, Li L, Sun L. DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis. Acta Pharmacol Sin 2024; 45:777-789. [PMID: 38200148 PMCID: PMC10943083 DOI: 10.1038/s41401-023-01216-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 12/11/2023] [Indexed: 01/12/2024]
Abstract
Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.
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Affiliation(s)
- Ming Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Yan Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Shi-Lu Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Chong-Bin Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Na Jiang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Chen-Rui Li
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Hao Zhao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Ya-Chun Han
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Li Li
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China.
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Cui P, Chen C, Cui Y, Qiu X, Yue K, Li T, Zhang H, Yuan W, Xie Y, Guo Y, Tang Z, Li Y, Peng F, Jiang X, Luo X, Peng L, Qi Z, Dai H. DsbA-L deletion attenuates LPS-induced acute kidney injury by modulating macrophage polarization. Eur J Immunol 2023; 53:e2250071. [PMID: 37379419 DOI: 10.1002/eji.202250071] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 05/28/2023] [Accepted: 06/27/2023] [Indexed: 06/30/2023]
Abstract
Disulfide bond A oxidoreductase-like protein (DsbA-L) drives acute kidney injury (AKI) by directly upregulating the expression of voltage-dependent anion-selective channels in proximal tubular cells. However, the role of DsbA-L in immune cells remains unclear. In this study, we used an LPS-induced AKI mouse model to assess the hypothesis that DsbA-L deletion attenuates LPS-induced AKI and explore the potential mechanism of DsbA-L action. After 24 hours of LPS exposure, the DsbA-L knockout group exhibited lower serum creatinine levels compared to the WT group. Furthermore, peripheral levels of the inflammatory cytokine IL-6 were decreased. Transcriptomic data analysis revealed a significant down-regulation in the IL-17 and tumor necrosis factor pathways in DsbA-L knockout mice following LPS induction. Metabolomic analysis suggested that arginine metabolism was significantly different between the WT and DsbA-L knockout groups after LPS treatment. Notably, the M1 polarization of macrophages in the kidneys of DsbA-L knockout AKI mice was significantly reduced. Expression of the transcription factors NF-κB and AP-1 was downregulated after DsbA-L knockout. Our results suggest that DsbA-L regulates LPS-mediated oxidative stress, promotes M1 polarization of macrophages, and induces expression of inflammatory factors via the NF-κB/AP-1 pathway.
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Affiliation(s)
- Pengcheng Cui
- Medical College, Guangxi University, Nanning, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chao Chen
- Medical College, Guangxi University, Nanning, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Cui
- Medical College, Guangxi University, Nanning, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Qiu
- Medical College, Guangxi University, Nanning, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Kaiye Yue
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Tengfang Li
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hedong Zhang
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wenjia Yuan
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yixin Xie
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yong Guo
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhouqi Tang
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yaguang Li
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fenghua Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, China
| | - Xuewei Luo
- Medical College, Guangxi University, Nanning, China
| | - Longkai Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhongquan Qi
- Medical College, Guangxi University, Nanning, China
| | - Helong Dai
- Medical College, Guangxi University, Nanning, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
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11
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Lu S, Li Y, Qian Z, Zhao T, Feng Z, Weng X, Yu L. Role of the inflammasome in insulin resistance and type 2 diabetes mellitus. Front Immunol 2023; 14:1052756. [PMID: 36993972 PMCID: PMC10040598 DOI: 10.3389/fimmu.2023.1052756] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
The inflammasome is a protein complex composed of a variety of proteins in cells and which participates in the innate immune response of the body. It can be activated by upstream signal regulation and plays an important role in pyroptosis, apoptosis, inflammation, tumor regulation, etc. In recent years, the number of metabolic syndrome patients with insulin resistance (IR) has increased year by year, and the inflammasome is closely related to the occurrence and development of metabolic diseases. The inflammasome can directly or indirectly affect conduction of the insulin signaling pathway, involvement the occurrence of IR and type 2 diabetes mellitus (T2DM). Moreover, various therapeutic agents also work through the inflammasome to treat with diabetes. This review focuses on the role of inflammasome on IR and T2DM, pointing out the association and utility value. Briefly, we have discussed the main inflammasomes, including NLRP1, NLRP3, NLRC4, NLRP6 and AIM2, as well as their structure, activation and regulation in IR were described in detail. Finally, we discussed the current therapeutic options-associated with inflammasome for the treatment of T2DM. Specially, the NLRP3-related therapeutic agents and options are widely developed. In summary, this article reviews the role of and research progress on the inflammasome in IR and T2DM.
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Affiliation(s)
- Shen Lu
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Yanrong Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhaojun Qian
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Tiesuo Zhao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xiaogang Weng
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
- *Correspondence: Lili Yu, ; Xiaogang Weng,
| | - Lili Yu
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
- *Correspondence: Lili Yu, ; Xiaogang Weng,
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12
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Hyperoside attenuates Cd-induced kidney injury via inhibiting NLRP3 inflammasome activation and ROS/MAPK/NF-κB signaling pathway in vivo and in vitro. Food Chem Toxicol 2023; 172:113601. [PMID: 36610472 DOI: 10.1016/j.fct.2023.113601] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/31/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023]
Abstract
Cadmium accumulates in the kidney and causes inflammation. The NLRP3 inflammasome has been linked to the pathogenesis of inflammation. Hyperoside (HYP) possesses potent nephroprotective properties against of kidney injury. This study aimed to research the effects and related mechanism of HYP on Cd-induced kidney damage. Wide-type and NLRP3-/- mice were used to determine the role of NLRP3 inflammasome in Cd-induced renal dysfunction. Female C57BL/6 were treated with Cd (50 m,g/L) and HYP (25, 50 mg/kg) for 12 weeks. In vitro experiments, the human renal proximal-tubule epithelial cells (RPTEC/TERT1) were pretreated with HYP (50-200 μM) before exposure to Cd. NLRP3 deficiency attenuated Cd-induced NLRP3 activation, inflammation and kidney injury in mice. HYP treatment significantly alleviated Cd-induced kidney injury by decreasing indexes of kidney function, reducing pro-inflammatory cytokines release, decreasing ROS production and suppressing NLRP3 inflammasome activation. Moreover, treatment with siRNA targeting NLRP3 blocked the anti-inflammatory protective effect of HYP in Cd-treated cells. Additionally, HYP markedly inhibited Cd-induced MAPK/NF-κB pathway stimulation in vitro and in vivo. The findings indicated HYP conferred protection against Cd-induced kidney inflammation via suppression of NLRP3 inflammasome mediated by ROS/MAPK/NF-κB signaling. Our results thus support the notion of developing HYP as promising therapeutic candidate for Cd-induced kidney injury.
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13
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Ala M. Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy. J Diabetes Res 2023; 2023:8776878. [PMID: 36818747 PMCID: PMC9937769 DOI: 10.1155/2023/8776878] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/22/2022] [Accepted: 02/04/2023] [Indexed: 02/12/2023] Open
Abstract
Sestrin2 regulates cell homeostasis and is an upstream signaling molecule for several signaling pathways. Sestrin2 leads to AMP-activated protein kinase- (AMPK-) and GTPase-activating protein activity toward Rags (GATOR) 1-mediated inhibition of mammalian target of rapamycin complex 1 (mTORC1), thereby enhancing autophagy. Sestrin2 also improves mitochondrial biogenesis via AMPK/Sirt1/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) signaling pathway. Blockade of ribosomal protein synthesis and augmentation of autophagy by Sestrin2 can prevent misfolded protein accumulation and attenuate endoplasmic reticulum (ER) stress. In addition, Sestrin2 enhances P62-mediated autophagic degradation of Keap1 to release nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 release by Sestrin2 vigorously potentiates antioxidant defense in diabetic nephropathy. Impaired autophagy and mitochondrial biogenesis, severe oxidative stress, and ER stress are all deeply involved in the development and progression of diabetic nephropathy. It has been shown that Sestrin2 expression is lower in the kidney of animals and patients with diabetic nephropathy. Sestrin2 knockdown aggravated diabetic nephropathy in animal models. In contrast, upregulation of Sestrin2 enhanced autophagy, mitophagy, and mitochondrial biogenesis and suppressed oxidative stress, ER stress, and apoptosis in diabetic nephropathy. Consistently, overexpression of Sestrin2 ameliorated podocyte injury, mesangial proliferation, proteinuria, and renal fibrosis in animal models of diabetic nephropathy. By suppressing transforming growth factor beta (TGF-β)/Smad and Yes-associated protein (YAP)/transcription enhancer factor 1 (TEF1) signaling pathways in experimental models, Sestrin2 hindered epithelial-mesenchymal transition and extracellular matrix accumulation in diabetic kidneys. Moreover, modulation of the downstream molecules of Sestrin2, for instance, augmentation of AMPK or Nrf2 signaling and inhibition of mTORC1, has been protective in diabetic nephropathy. Regarding the beneficial effects of Sestrin2 on diabetic nephropathy and its interaction with several signaling molecules, it is worth targeting Sestrin2 in diabetic nephropathy.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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14
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Bai F, Yu K, Yang Y, Zhang Y, Ding L, An X, Feng F, Sun N, Fan J, Liu L, Yang H, Yang X. Identification and validation of P4HB as a novel autophagy-related biomarker in diabetic nephropathy. Front Genet 2022; 13:965816. [PMID: 36226178 PMCID: PMC9548632 DOI: 10.3389/fgene.2022.965816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic nephropathy (DN), a frequent microvascular complication of diabetes, has been recognized as a primary cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Previous studies found that autophagy of renal tubular epithelial cells plays an important role in DN pathogenesis. Our research aimed to investigate the differentially expressed autophagy-related genes (DEARGs) between DN and healthy renal tubule samples and identify a novel autophagy-related biomarker associated with tubulointerstitial injury in DN. In this study, gene expression profiles of renal tubules from 10 DN patients and 24 healthy controls in the GSE30122 dataset were analyzed, and 43 DEARGs were identified by bioinformatics analysis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and correlation analysis were performed on DEARGs, and the hub gene prolyl 4-hydroxylase subunit beta (P4HB) was screened by protein–protein interaction and verified by utilizing other datasets and stimulating HK-2 cells under high glucose concentration. We found that the expression of P4HB in renal tubules was correlated with renal function. In summary, our research provided novel insights for comprehension of DN molecular mechanisms and identified P4HB as a novel autophagy-related biomarker of DN.
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Affiliation(s)
- Fang Bai
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Kuipeng Yu
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yanjiang Yang
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yimeng Zhang
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lin Ding
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xin An
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Feng Feng
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Nan Sun
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jiahui Fan
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lei Liu
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Huimin Yang
- Department of General Practice, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiangdong Yang
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- *Correspondence: Xiangdong Yang,
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15
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Liu C, Yang M, Li L, Luo S, Yang J, Li C, Liu H, Sun L. A Glimpse of Inflammation and Anti-Inflammation Therapy in Diabetic Kidney Disease. Front Physiol 2022; 13:909569. [PMID: 35874522 PMCID: PMC9298824 DOI: 10.3389/fphys.2022.909569] [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: 04/04/2022] [Accepted: 05/18/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a common complication of diabetes mellitus and a major cause of end-stage kidney disease (ESKD). The pathogenesis of DKD is very complex and not completely understood. Recently, accumulated evidence from in vitro and in vivo studies has demonstrated that inflammation plays an important role in the pathogenesis and the development of DKD. It has been well known that a variety of pro-inflammatory cytokines and related signaling pathways are involved in the procession of DKD. Additionally, some anti-hyperglycemic agents and mineralocorticoid receptor antagonists (MRAs) that are effective in alleviating the progression of DKD have anti-inflammatory properties, which might have beneficial effects on delaying the progression of DKD. However, there is currently a lack of systematic overviews. In this review, we focus on the novel pro-inflammatory signaling pathways in the development of DKD, including the nuclear factor kappa B (NF-κB) signaling pathway, toll-like receptors (TLRs) and myeloid differentiation primary response 88 (TLRs/MyD88) signaling pathway, adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathways, inflammasome activation, mitochondrial DNA (mtDNA) release as well as hypoxia-inducible factor-1(HIF-1) signaling pathway. We also discuss the related anti-inflammation mechanisms of metformin, finerenone, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, Dipeptidyl peptidase-4 (DPP-4) inhibitors, Glucagon-like peptide-1 (GLP-1) receptor agonist and traditional Chinese medicines (TCM).
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Affiliation(s)
- Chongbin Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China.,Hunan Key Laboratory of kidney Disease and Blood Purification, Changsha, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China.,Hunan Key Laboratory of kidney Disease and Blood Purification, Changsha, China
| | - Li Li
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China.,Hunan Key Laboratory of kidney Disease and Blood Purification, Changsha, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China
| | - Chenrui Li
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China
| | - Huafeng Liu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases & Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South Unibersity, Changsha, China.,Hunan Key Laboratory of kidney Disease and Blood Purification, Changsha, China
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16
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lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis. J Immunol Res 2022; 2022:8098001. [PMID: 35910856 PMCID: PMC9334040 DOI: 10.1155/2022/8098001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/01/2022] [Indexed: 02/07/2023] Open
Abstract
Objective The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are closely associated with the pathogenesis of diabetic nephropathy (DN). But a complete mechanism for MALAT1 in DN has yet to be identified. This study investigated the effect of MALAT1 on DN through the regulation of miR-15b-5p/TLR4 signaling. Method Renal tissues were collected from DN patients. Human renal tubular epithelial cells (HK-2) were used as a model of DN induced by high glucose (HG). We then measured the viability, apoptosis, and inflammatory cytokine levels of HK-2 cells using the corresponding assays. Following transfections of si-MALAT1, si-MALAT1+miR-15b-5p inhibitor, or si-MALAT1+vector TLR4 into HG-stimulated HK-2 cells, cell viability, apoptosis, and inflammatory cytokines were again measured. Furthermore, dual-luciferase reporter assay validated the interactions of MALAT1/miR-15b-5p and miR-15b-5p/TLR4. In addition, the interaction between MALAT1 and miR-15b-5p was investigated by RNA immunoprecipitation (RIP). Results A significant upregulation of MALAT1 was observed in DN kidney tissues, as well as in HG-stimulated HK-2 cells. MALAT1 knockdown attenuates the inhibition of cell viability, apoptosis, and inflammatory response induced by HG in HK-2 cells. Moreover, a miR-15b-5p inhibitor or TLR4 overexpression reversed the above effects induced by MALAT1 knockdown. Conclusion These results indicate that reduced MALAT1 ameliorates HG-stimulated HK-2 cell damage through an inhibition of the miR-15b-5p/TLR4 axis. MALAT1 may serve as a biomarker and potential therapeutic target for DN.
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17
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Liu J, Yang J. Mitochondria-associated membranes: A hub for neurodegenerative diseases. Biomed Pharmacother 2022; 149:112890. [PMID: 35367757 DOI: 10.1016/j.biopha.2022.112890] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 11/02/2022] Open
Abstract
In eukaryotic cells, organelles could coordinate complex mechanisms of signaling transduction metabolism and gene expression through their functional interactions. The functional domain between ER and mitochondria, called mitochondria-associated membranes (MAM), is closely associated with various physiological functions including intracellular lipid transport, Ca2+ transfer, mitochondria function maintenance, and autophagosome formation. In addition, more evidence suggests that MAM modulate cellular functions in health and disease. Studies have also demonstrated the association of MAM with numerous diseases, including neurodegenerative diseases, cancer, viral infection, obesity, and diabetes. In fact, recent evidence revealed a close relationship of MAM with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. In this view, elucidating the role of MAM in neurodegenerative diseases is particularly important. This review will focus the main tethering protein complexes of MAM and functions of MAM. Besides, the role of MAM in the regulation of neurodegenerative diseases and the potential molecular mechanisms is introduced to provide a new understanding of the pathogenesis of these diseases.
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Affiliation(s)
- Jinxuan Liu
- Department of Toxicology, School of Public Health, China Medical University, NO.77 Puhe road, Shenyang North New Area, Shenyang, 110122, People's Republic of China.
| | - Jinghua Yang
- Department of Toxicology, School of Public Health, China Medical University, NO.77 Puhe road, Shenyang North New Area, Shenyang, 110122, People's Republic of China.
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18
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El-Maadawy WH, Hassan M, Abdou RM, El-Dine RS, Aboushousha T, El-Tanbouly ND, El-Sayed AM. 6-Paradol alleviates Diclofenac-induced acute kidney injury via autophagy enhancement-mediated by AMPK/AKT/mTOR and NLRP3 inflammasome pathways. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 91:103817. [PMID: 35091105 DOI: 10.1016/j.etap.2022.103817] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/10/2021] [Accepted: 01/19/2022] [Indexed: 06/14/2023]
Abstract
Diclofenac (DIC)-induced acute kidney injury (AKI) causes high morbidity and mortality. With the absence of satisfactory treatment, we investigated the protective effects of 6-Paradol (PDL) against DIC-induced AKI, with focus on renal autophagy and NLRP3 inflammasome pathways . PDL has anti-inflammatory, antioxidant and AMPK-activation properties. PDL was administered to DIC-challenged rats. Nephrotoxicity, oxidative stress, inflammatory, and autophagy markers and histopathological examinations were evaluated. Compared to DIC, PDL restored serum nephrotoxicity, renal oxidative stress and pro-inflammatory markers. PDL almost restored renal architecture, upregulated renal Nrf2 pathway via enhancing Nrf2 mRNA expression and HO-1 levels. PDL suppressed renal NF-κB mRNA expression, and NLRP3 inflammasome pathway expression. Moreover, PDL enhanced renal autophagy through upregulating LC3B, AMPK and SIRT-1, and suppressed mTOR, p-AKT mRNA expressions and phosphorylated-p62 levels. Our study confirmed that autophagy suppression mediates DIC-induced AKI via AMPK/mTOR/AKT and NLRP3-inflammasome pathways. Also, PDL's nephroprotective effects could provide a promising therapeutic approach against DIC-induced AKI.
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Affiliation(s)
- Walaa H El-Maadawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza 12411, Egypt.
| | - Marwa Hassan
- Department of Immunology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza 12411, Egypt
| | - Rabab M Abdou
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
| | - Riham S El-Dine
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
| | - Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza 12411, Egypt
| | - Nebal D El-Tanbouly
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
| | - Aly M El-Sayed
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
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19
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Kong L, Zhang H, Lu C, Shi K, Huang H, Zheng Y, Wang Y, Wang D, Wang H, Huang W. AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation. Front Pharmacol 2021; 12:724514. [PMID: 34531748 PMCID: PMC8438129 DOI: 10.3389/fphar.2021.724514] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.
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Affiliation(s)
- Lijun Kong
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hewei Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chaosheng Lu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongjian Huang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yushu Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongqiang Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dan Wang
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongwei Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Huang
- Department of Nutrition, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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