MicroRNA-27a Induces Mesangial Cell Injury by Targeting of PPARγ and its In Vivo Knockdown Prevents Progression of Diabetic Nephropathy

Podocyte injury has a pivotal role in the pathogenesis of diabetic nephropathy (DN). MicroRNA-27a (miR-27a), peroxisome proliferator-activated receptor γ (PPARγ) and β-catenin pathways have been involved in the pathogenesis of DN. Herein, we asked whether miR-27a mediates podocyte injury through PPARγ/β-catenin signaling in DN. The functional relevance of miR-27a, PPARγ and β-catenin were investigated in cultured podocytes and glomeruli of diabetic rats and patients using in vitro and in vivo approaches. Podocyte injury was assessed by migration, invasion and apoptosis assay. Biological parameters were analyzed using enzyme-linked immunosorbent assay. We found that high glucose stimulated miR-27a expression, which, by negatively targeting PPARγ, activated β-catenin signaling as evidenced by upregulation of β-catenin target genes, snail1 and α-smooth muscle actin (α-SMA) and downregulation of podocyte-specific markers podocin and synaptopodin. These changes caused podocyte injury as demonstrated by increased podocyte mesenchymal transition, disrupted podocyte architectural integrity and increased podocyte apoptosis. Furthermore, we provide evidence that miR-27a contributed to unfavorable renal function and increased podocyte injury in diabetic rats. Notably, miR-27a exhibited clinical and biological relevance as it was linked to elevated serum creatinine, proteinuria and reduced creatinine clearance rate. In addition, miR-27a upregulation and activation of PPARγ/β-catenin signaling were verified in renal biopsy samples from DN patients. We propose a novel role of the miR-27a/PPARγ/β-catenin axis in fostering the progression toward more deteriorated podocyte injury in DN. Targeting miR-27a could be a potential therapeutic approach for DN.

show abstract

“…20, 26 In this study, our aim was to explore whether miR-27a promotes podocyte injury through PPAR γ -mediated β -catenin activation in DN.…”

mentioning

confidence: 99%

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

et al. 2017

View full text Add to dashboard Cite

show abstract

“…And, micro-RNA23 can be mediated by PPARc in renal calcium oxalate crystal formation. lncRNA TUG1 could modulate ECM accumulation in DN by regulating miR-377 targeting PPARc [48][49][50]. However, the role of the epigenetic modification in PPARc function in kidney diseases still needs further exploration.…”

Section: Pparγ and Kidney Fibrosismentioning

confidence: 99%

PPARγ and Its Agonists in Chronic Kidney Disease

Shi

Wang

et al. 2020

International Journal of Nephrology

View full text Add to dashboard Cite

Chronic kidney disease (CKD) has become a global healthcare issue. CKD can progress to irreversible end-stage renal diseases (ESRD) or renal failure. e major risk factors for CKD include obesity, diabetes, and cardiovascular diseases. Understanding the key process involved in the disease development may lead to novel interventive strategies, which is currently lagging behind. Peroxisome proliferator-activated receptor c (PPARc) is one of the ligand-activated transcription factor superfamily members and is globally expressed in human tissues. Its agonists such as thiazolidinediones (TZDs) have been applied as effective antidiabetic drugs as they control insulin sensitivity in multiple metabolic tissues. Besides, TZDs exert protective effects in multiple other CKD risk disease contexts. As PPARc is abundantly expressed in major kidney cells, its physiological roles in those cells have been studied in both cell and animal models. e function of PPARc in the kidney ranges from energy metabolism, cell proliferation to inflammatory suppression, although major renal side effects of existing agonists (including TZDs) have been reported, which limited their application in treating CKD. In the current review, we systemically assess the function of PPARc in CKDs and the benefits and current limitations of its agonists in the clinical applications.

show abstract

“…There is in vivo evidence that microRNA (miR)-29c knockdown or miR-27a knockdown compromises progression of diabetic nephropathy. [8,9] Furthermore, Chien et al [10] have found that miR-21, miR-29a/b/c, and miR-192 are involved in pathogenesis of diabetic neuropathy and might be suggested as biomarkers of progression of diabetic neuropathy. Despite these achievements, the molecular mechanisms behind the diabetic neuropathy have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Identification of genes and signaling pathways associated with diabetic neuropathy using a weighted correlation network analysis

Xie

et al. 2016

Medicine

View full text Add to dashboard Cite

Background:The molecular mechanisms behind diabetic neuropathy remains to be investigated.Methods:This is a secondary study on microarray dataset (GSE24290) downloaded from Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI), which included 18 nerve tissue samples of progressing diabetic neuropathy (fibers loss ≥500 fibers/mm2) and 17 nerve tissue samples of nonprogressing diabetic neuropathy (fibers loss ≤100 fibers/mm2). Differentially expressed genes (DEGs) were screened between progressing and nonprogressing diabetic neuropathy. With the DEGs obtained, a weighted gene coexpression network analysis was conducted to identify gene clusters associated with diabetic neuropathy. Diabetes-related microRNAs (miRNAs) and their target genes were predicted and mapped to the genes in the gene clusters identified. Consequently, a miRNA–gene network was constructed, for which gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. Potential drugs for treatment of diabetic neuropathy were also predicted.Results:Total 370 upregulated and 379 downregulated DEGs were screened between nonprogressing and progressing diabetic neuropathy. Has-miR-377, has-miR-216a, and has-miR-217 were associated with diabetes. Inflammation was the most significant GO term. The peroxisome proliferator-activated receptor (PPAR) pathway and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway were significantly KEGG pathways significantly enriched with PPAR gamma (PPARG), stearoyl-CoA desaturase (SCD), cluster of differentiation 36 (CD36), and phosphoenolpyruvate carboxykinase 1 (PCK1).Conclusion:The study suggests that PPARG, SCD, CD36, PCK1, AMPK pathway, and PPAR pathway may be involved in progression of diabetic neuropathy.

show abstract

MicroRNA-27a Induces Mesangial Cell Injury by Targeting of PPARγ and its In Vivo Knockdown Prevents Progression of Diabetic Nephropathy

Cited by 59 publications

References 40 publications

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

PPARγ and Its Agonists in Chronic Kidney Disease

Identification of genes and signaling pathways associated with diabetic neuropathy using a weighted correlation network analysis

Contact Info

Product

Resources

About