DsbA-L Ameliorates Renal Injury Through the AMPK/NLRP3 Inflammasome Signaling Pathway in Diabetic Nephropathy.
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ABSTRACT:
SUBMITTER: Yang M
PROVIDER: S-EPMC8120163 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-?1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1? in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL-22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1? pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN.
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Project description:Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-? and PGC-1?. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-? or PGC-1? short interfering RNA. In addition, Rap1b could modulate C/EBP-? binding to the endogenous PGC-1? promoter and the interaction between PGC-1? and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-?-PGC-1? signaling.
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Project description:Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-?B) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-?B among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-?B pathway by directly interacting with p50, the subunit of NF-?B. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-?B/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.
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Project description:Diabetic nephropathy (DN) is a primary cause of end‑stage renal disease. Despite the beneficial effects of astragaloside IV (AS)‑IV on renal disease, the underlying mechanism of its protective effects against DN has not been fully determined. The aims of the present study were to assess the effects of AS‑IV against DN in db/db mice and to explore the mechanism of AS‑IV involving the NLR family pyrin domain containing 3 (NLRP3), caspase‑1 and interleukin (IL)‑1β pathways. The 8‑week‑old db/db mice received 40 mg/kg AS‑IV once a day for 12 weeks via intragastric administration. Cultured mouse podocytes were used to further confirm the underlying mechanism in vitro. AS‑IV effectively reduced weight gain, hyperglycemia and the serum triacylglycerol concentration in db/db mice. AS‑IV also reduced urinary albumin excretion, urinary albumin‑to‑creatinine ratio and creatinine clearance rate, as well as improved renal structural changes, accompanied by the upregulation of the podocyte markers podocin and synaptopodin. AS‑IV significantly inhibited the expression levels of NLRP3, caspase‑1 and IL‑1β in the renal cortex, and reduced the serum levels of tumor necrosis factor (TNF)‑α and monocyte chemoattractant protein‑1. In high glucose‑induced podocytes, AS‑IV significantly improved the expression levels of NLRP3, pro‑caspase‑1 and caspase‑1, and inhibited the cell viability decrease in a dose‑dependent manner, while NLRP3 overexpression eliminated the effect of AS‑IV on podocyte injury and the inhibition of the NLRP3 and caspase‑1 pathways. The data obtained from in vivo and in vitro experiments demonstrated that AS‑IV ameliorated renal functions and podocyte injury and delayed the development of DN in db/db mice via anti‑NLRP3 inflammasome‑mediated inflammation.
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Project description:Diabetic nephropathy (DN) is a common complication of diabetes and an important cause of end-stage renal disease. Increasing evidence suggests that microRNAs (miRNAs) regulate the development of DN. In a preliminary study, high levels of miR-150-5p were detected in the serum and urine of patients with DN. Consequently, we investigated the effect and mechanism of action of miR-150-5p in DN in vitro and in vivo. Our results showed that inhibition of miR-150-5p reversed high glucose-induced podocyte injury and Streptozocin (STZ)-induced diabetic nephropathy in mice. Further analysis revealed that miR-150-5p targeted the 3' untranslated region (UTR) of sirtuin 1 (SIRT1), consequently decreasing SIRT1 levels in podocytes. Importantly, we found that the silencing of miR-150-5p promoted the interaction between SIRT1 and p53, causing the suppression of p53 acetylation in podocytes and kidney tissue. This resulted in the stimulation of AMP-activated protein kinase (AMPK)-dependent autophagy. In conclusion, our study demonstrated that the silencing of miR-150-5p played a reno-protective role in DN mice through targeting SIRT1.
| S-EPMC8064124 | biostudies-literature
Project description:Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.
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Project description:Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator nigericin abolished the anti-inflammatory effects of metformin in NRVMs, but it had little effect on AMPK phosphorylation. Collectively, our study confirmed that metformin exerts cardioprotective effects by regulating myocardial I/R injury-induced inflammatory response, which was largely dependent on the enhancement of the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.
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Project description:Progressive reduction of SnoN is associated with gradual elevation of TGF-β1 during diabetic nephropathy progression, suggesting SnoN to be a possible mediator of TGF-β1 signaling, with potential therapeutic benefits against TGF- β1 -induced renal fibrosis. To characterize SnoN for its role in renal fibrosis, we assessed SnoN expression patterns in response to high glucose stress, and evaluated the effects of upregulating SnoN on renal fibrosis. High glucose stress induced significantly elevated SnoN, TGF-β1, and Arkadia transcription; however, significantly reduced SnoN protein levels were observed under these conditions. Upregulating the SnoN protein was achieved by Arkadia knockdown, which resulted in inhibited high glucose-induced epithelial-mesenchymal transition (EMT) in renal tubular cells, the onset phase of renal fibrosis. Alternatively, EMT was suppressed by dominantly expressed exogenous SnoN without interfering with TGF-β1. Overall, renal SnoN upregulation ameliorates renal fibrosis by relieving high glucose-induced EMT; these findings support a translational approach targeting SnoN for the treatment of diabetic nephropathy.
| S-EPMC5370123 | biostudies-literature
Project description:BackgroundDiabetic nephropathy has been a devastating complication. Clinically, there is an urgent need for nephroprotective agents to delay the onset of diabetic nephropathy and ameliorate its symptoms. Maslinic acid is a pentacyclic triterpene acid with protective effect on multiple organs against oxidative stress and inflammation. In this research, we hypothesized that maslinic acid protects renal function against diabetic nephropathy.MethodsC57BL/6 J male mice administrated with 50 mg/kg of Streptozocin (STZ) daily were used to establish diabetic mouse model (blood glucose levels > 300 mg/dL). Urinary levels of albumin, total proteins, and creatinine were analyzed by an automatic analyzer. H&E staining was used to evaluate renal damage. qRT-PCR and ELISA were performed to investigate the inflammation and oxidative stress in renal tissues. Western blot was used to assess the activation of AMPK signaling.ResultsMaslinic acid treatment alleviated the loss of body weight and blood glucose in diabetic mice. Renal structure and function were protected by maslinic acid in diabetic mice. 20 mg/kg maslinic acid treatment for 8 weeks significantly alleviated the oxidative stress and inflammation in the kidney of diabetic rats. Maslinic acid treatment activated the renal AMPK/SIRT1 signaling pathway.ConclusionMaslinic acid ameliorates diabetic nephropathy and activates the renal AMPK/SIRT1 signaling pathway.
| S-EPMC8767743 | biostudies-literature
Project description:BackgroundDiabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem.ObjectiveTo evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM.MethodsPancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD).ResultsIslet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined.ConclusionsDN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy.
| S-EPMC5488369 | biostudies-literature