The Wnt Signaling Pathway in Diabetic Nephropathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang H
PROVIDER: S-EPMC8763969 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Diabetic nephropathy (DN) is one of the serious chronic microvascular complications of diabetes, and leads to the increased morbidity and mortality in diabetic patients. Gasdermin E (GSDME)-dependent pyroptosis signaling pathway plays important roles in a variety of physiological and pathological processes. However, its role and mechanism in DN are still unclear. In this study, we established a rat DN model by intraperitoneal injection of streptozotocin (STZ) successfully. Structural and functional disorders in the kidney were exhibited on the 12th week after STZ injection; the expressions of caspase-3 and GSDME at protein level in renal cortex were significantly up-regulated. At the 20th week, GSDME-N increased significantly, accompanied by the upregulation of caspase-1 in renal cortex and the release of mature IL-1β (mIL-1β) in serum. Furthermore, we found the protein levels of GSDME, caspase-3, caspase-1 and IL-1β were all increased in HK2 and HBZY-1 cells under high-glucose conditions. We also found that the expression of GSDME-N significantly decreased when caspase-3 was knockdown. In contrast, knockdown of GSDME has no effect on caspase-3. Interestingly, either caspase-3, caspase-1 or GSDME knockdown reduced the release of mIL-1β. Finally, injection of adeno-associated virus (AAV) 9-shGSDME into the rat kidney reduced kidney damage and renal cell pyroptosis in comparison with wild-type diabetic rats. These results indicated that the activation of caspase-1 induced IL-1β maturation, and the activation of caspase-3 mediated cleavage of GSDME responsible for the formation of plasma membrane pore, followed by cytoplasmic release of mIL-1β. Overall, we identified a pro-pyroptosis role for GSDME in DN, which does provide an important basis for clinical therapeutic studies.
| S-EPMC10175547 | biostudies-literature
Project description:AimA recent meta-analysis of genome-wide linkage studies (GWLS) has identified multiple genetic regions suggestive of linkage with DN harboring hundreds of genes. Moving this number of genetic loci forward into biological insight is truly the next step. Here, we approach this challenge with a gene ontology (GO) analysis in order to yield biological and functional role to the genes, an over-representation test to find which GO terms are enriched in the gene list, pathway analysis, as well as protein network analysis.MethodGO analysis was performed using protein analysis through evolutionary relationships (PANTHER) version 14.0 software and P-values less than 0.05 were considered statistically significant. GO analysis was followed by over-representation test for the identification of enriched terms. Statistical significance was calculated by Fisher's exact test and adjusted using the false discovery rate (FDR) for correction of multiple tests. Cytoscape with the relevant plugins was used for the construction of the protein network and clustering analysis.ResultsThe GO analysis assign multiple GO terms to the genes regarding the molecular function, the biological process and the cellular component, protein class and pathway analysis. The findings of the over-representation test highlight the contribution of cell adhesion regarding the biological process, integral components of plasma membrane regarding the cellular component, chemokines and cytokines with regard to protein class, while the pathway analysis emphasizes the contribution of Wnt and cadherin signaling pathways.ConclusionsOur results suggest that a core feature of the pathogenesis of DN may be a disturbance in Wnt and cadherin signaling pathways, whereas the contribution of chemokines and cytokines need to be studied in additional studies.
| S-EPMC8375992 | biostudies-literature
Project description:The effects of Liuwei Dihuang pill (LWDH) on diabetic nephropathy-related osteoporosis (DNOP) are unclear. The present study aimed to evaluate the effects of LWDH on KDM7A and Wnt/β-catenin signaling pathway in DNOP rats and the high glucose-induced MC3T3-E1 cells. A DNOP model was prepared by streptozotocin in 9-week-old male Sprague-Dawley (SD) rats to evaluate the effects of LWDH. The cell viability and differentiation capacity of high glucose-induced MC3T3-E1 cells were determined by CCK-8 assay, Alizarin Red staining, and alkaline phosphatase (ALP) staining, respectively. Furthermore, the expressions of KDM7A and Wnt1/β-catenin pathway-related proteins were determined by Western blot analysis. Treatment of DNOP rats with LWDH could significantly ameliorate the general state, degradation of renal function, and renal pathological changes. LWDH decreased the levels of TNF-α, IL-6, IL-8, IL-1β, ALP, and TRAP, and increased the calcium, phosphorus in serum, as well as decreased the level of the calcium and phosphorus in the urine. Besides, LWDH significantly improved bone mineral density (BMD), bone volume (BV), and the bone microstructure of DNOP rats. Moreover, LWDH increased the levels of the elastic modulus, ultimate load, and bending strength in the femurs. In MC3T3-E1 cells, serum-containing LWDH significantly increases in cell viability and osteoblastic differentiation capability. The expression of α-SMA, vimentin, KDM7A, Wnt1 and β-catenin were significantly down-regulated, and the E-cadherin, H3K9-Me2, H3K27-Me2, BMP-4, BMP-7, Runx2, osteocalcin, and Col1a1 were significantly up-regulated with LWDH treatment. The present study shows that LWDH has a therapeutic effect on DNOP, in part, through down-regulation of KDM7A and Wnt/β-catenin pathway.
| S-EPMC7502694 | biostudies-literature
Project description:BackgroundDiabetic nephropathy (DN) is one of the principal complications of diabetes and podocyte injury plays an important role in the DN pathogenesis. Wnt/β-catenin signaling overactivation confers podocyte injury and promotes multiple types of renal disease. However, the underlying mechanism of Wnt/β-catenin signaling activation in DN progression has not been fully elucidated. Long noncoding RNA (lncRNA) is a large class of endogenous RNA molecules lacking functional code capacity and which participates in the pathogenesis of human disease, including DN.MethodA diabetes model was constructed by intraperitoneal injection of Streptozotocin in rats. The MPC5 cells were used to create the in vitro model. Western blot and Quantitative reverse-transcriptase-PCR were used to examine the expression of protein and mRNA. The migrated capacity was analyzed by Transwell migration assay. The cell viability was detected by CCK8.ResultsIn the present study, we revealed the association of lncRNA Maternally Expressed Gene 3 (MEG3) with aberrant activation of Wnt/β-catenin signaling and the role of MEG3/Wnt axis in podocyte injury. We found that high glucose (HG) treatment suppressed MEG3 expression in cultured podocytes, activated Wnt/β-catenin signaling and caused podocyte injury as indicated by the downregulation of podocyte-specific markers (podocin and synaptopodin) and the upregulation of snail1 and α-smooth muscle actin. Overexpression of MEG3 attenuated HG-induced podocyte injury by reducing Wnt/β-catenin activity, repressing cell migration, reactive oxygen species production and increasing the viability of podocytes. Furthermore, we provided evidences that restoration of Wnt/β-catenin signaling by specific agonist impeded the protective effect of MEG3 on podocyte injury. Current results demonstrated that MEG3/Wnt axis plays an important role in fostering podocyte injury and may serve as a potential therapeutic target for the treatment of DN.ConclusionlncRNA MEG3 ameliorates podocyte injury in DN via inactivating Wnt/β-catenin signaling.
| S-EPMC6885352 | biostudies-literature
Project description:Immune and inflammatory factors have emerged as key pathophysiological mechanisms in the progression of diabetic renal injury. Noncanonical Wnt5a signaling plays an essential role in obesity- or diabetes-induced metabolic dysfunction and inflammation, but its explicit molecular mechanisms and biological function in diabetic nephropathy (DN) remain unknown. In this study, we found that the expression of Wnt5a and CD146 in the kidney and the level of soluble form of CD146 (sCD146) in serum and urine samples were upregulated in DN patients compared to controls, and this alteration was correlated with the inflammatory process and progression of renal impairment. Blocking the activation of Wnt5a signaling with the Wnt5a antagonist Box5 prevented JNK phosphorylation and high glucose-induced inflammatory responses in db/db mice and high glucose-treated HK-2 cells. Similar effects were observed by silencing Wnt5a with small-interfering RNA (siRNA) in cultured HK-2 cells. Knockdown of CD146 blocked Wnt5a-induced expression of proinflammatory cytokines and activation of JNK, which suggests that CD146 is essential for the activation of the Wnt5a pathway. Finally, we confirmed that Wnt5a directly interacted with CD146 to activate noncanonical Wnt signaling in HK-2 cells. Taken together, our findings suggest that by directly binding to CD146, Wnt5a-induced noncanonical signaling is a contributing mechanism for renal tubular inflammation in diabetic nephropathy. The concentration of sCD146 in serum and urine could be a potential biomarker to predict renal outcomes in DN patients.
| S-EPMC7814016 | biostudies-literature
Project description:Aims/introductionThe role of the renal nitric oxide (NO) system in the pathophysiology of diabetic nephropathy constitutes a very challenging and fertile field for future investigation. The purpose of the present study was to investigate whether NO donors can attenuate diabetic renal fibrosis and apoptosis through modulating oxidative-and nitrosative-stress, and Wnt signaling using in vivo diabetic models.Materials and methodsDiabetic rat was induced by a single intraperitoneal injection of streptozotocin. Rats in each group were intraperitoneally given 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (1 U/kg/day) and vehicle for 28 and 56 consecutive days. Expression of the oxidative-and nitrosative-stress, and Wnt signaling components were examined in kidneys from diabetic animals by quantitative reverse transcription polymerase chain reaction, western blot analysis and immunohistochemical staining.ResultsNO donor treatment significantly reduced the ratio of kidney weight to bodyweight and proteinuria. This treatment also significantly restored the suppressive effect of diabetes on urinary NO2 + NO3 levels. Immunohistochemistry showed that NO donor treatment significantly reduced transforming growth factor (TGF)-β1, fibronectin, cleaved caspase-3 and triphosphate-biotin nick end-labeling expression in the glomeruli of diabetic rats. We found that diabetes promoted 8-hydroxy-2'-deoxyguanosine, and peroxynitrite expression coincided with reduced endothelial NO synthase expression in glomeruli. Interestingly, NO donor treatment completely removed oxidative stress and nitrosative stress, and restored endothelial NO synthase expression in diabetic renal glomeruli. Immunohistomorphometry results showed that NO donor treatment significantly restored suppressed Wnt5a expression and β-catenin immunoreactivities in glomeruli. Based on laser-captured microdissection for quantitative reverse transcription polymerase chain reaction, diabetes significantly increased TGF-β1, and fibronectin expression coincided with depressed Wnt5a expression. NO donor treatment reduced TGF-β1, fibronectin activation, and the suppressing effect of diabetes on Wnt5a and β-catenin expression in renal glomeruli.ConclusionsNO donor treatment alleviates extracellular matrix accumulation and apoptosis in diabetic nephropathy in vivo by not only preventing the diabetes-mediated oxidative and nitrostative stress, but also restoring downregulation of endothelial NO synthase expression and Wnt/β-catenin signaling. These findings suggest that modulation of NO is a viable alternative strategy for rescuing diabetic renal injury.
| S-EPMC4296700 | biostudies-literature
Project description:BackgroundDiabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood.MethodsTo delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN.ResultsAnalysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration.ConclusionsOverall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.
| S-EPMC9830686 | biostudies-literature
Project description:Background and aimsRadix Rehmanniae and Corni Fructus (RC) have been widely applied to treat diabetic nephropathy (DN) for centuries. But the mechanism of how RC plays the therapeutic role against DN is unclear as yet.MethodsThe information about RC was obtained from a public database. The active compounds of RC were screened by oral bioavailability (OB) and drug-likeness (DL). Gene ontology (GO) analysis was performed to realize the key targets of RC, and an active compound-potential target network was created. The therapeutic effects of RC active compounds and their key signal pathways were preliminarily probed via network pharmacology analysis and animal experiments.ResultsIn this study, 29 active compounds from RC and 64 key targets related to DN were collected using the network pharmacology method. The pathway enrichment analysis showed that RC regulated advanced glycosylation end product (AGE-) RAGE and IL-17 signaling pathways to treat DN. The animal experiments revealed that RC significantly improved metabolic parameters, inflammation renal structure, and function to protect the kidney against DN.ConclusionsThe results revealed the relationship between multicomponents and multitargets of RC. The administratiom of RC might remit the DM-induced renal damage through the AGE-RAGE signaling pathway to improve metabolic parameters and protect renal structure and function.
| S-EPMC7725584 | biostudies-literature
Project description:Aims/hypothesisSeveral studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been attenuated through Wnt pathway modulation in model systems implicating Wnt pathway members as potential therapeutic targets for the treatment of diabetic nephropathy. We assessed tag and potentially functional single nucleotide polymorphisms (SNPs; n = 31) in four key Wnt pathway genes (CTNNB1, AXIN2, LRP5 and LRP6) for association with diabetic nephropathy using a case-control design.MethodsSNPs were genotyped using Sequenom or Taqman technologies in 1351 individuals with type 1 diabetes (651 cases with nephropathy and 700 controls without nephropathy). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Adjustment for multiple testing was performed by permutation testing.ResultsFollowing logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR = 0.74; CI: 0.57-0.97; P = 0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228 and rs491347 both in LRP5) were marginally associated with diabetic nephropathy, but none of the associations were replicated in an independent dataset. Haplotype and subgroup analysis (according to duration of diabetes, and end-stage renal disease) also failed to reveal an association with diabetic nephropathy.Conclusions/interpretationOur results suggest that analysed common variants in CTNNB1, AXIN2, LRP5 and LRP6 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes or other members of the Wnt pathway, from involvement in the pathogenesis of diabetic nephropathy as our study had limited power to detect variants with small effect size.
| S-EPMC3158097 | biostudies-literature
Project description:In this study the role of CXCL6 in diabetic nephropathy (DN) was investigated. It was found to be overexpression in DN patients and DN rat model. And the expression of fibrosis-related cytokines was consistent with the expression of CXCL6. High glucose significantly increased the proliferation of rat renal fibroblasts NRK-49F cell and the expression of CXCL6. Knockdown of CXCL6 ameliorated the pro-proliferation effect of high glucose and decreased the expression of fibrosis-related cytokines, while CXCL6 overexpression exhibited the opposite phenomenon. Gene set enrichment analysis, Western blot and ELISA showed that Janus kinase-signal transducer and activator of transcription (JAK-STAT) and CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION signaling pathways were correlative with CXCL6. This data indicates that CXCL6 may promote fibrosis-related factors to accelerate the development of DN renal interstitial fibrosis by activating JAK/STAT3 signaling pathway. CXCL6 is promising to be a potential novel therapeutic target and candidate biomarker for JAK/STAT3 signaling for the treatment of DN.
| S-EPMC6442023 | biostudies-literature