Journal
CELL DEATH & DISEASE
Volume 8, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/cddis.2017.74
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Funding
- National Nature and Science Young Investigator Grant from the National Natural Science Foundation of China [81100496]
- Special Fund from Chinese Society of Nephrology [13030370422]
- Guangdong Natural Science Foundation [2016A030313581]
- Distinguished Young Scholar Fund from Nanfang Hospital [2015J009]
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Podocyte injury has a pivotal role in the pathogenesis of diabetic nephropathy (DN). MicroRNA-27a (miR-27a), peroxisome proliferator-activated receptor gamma (PPAR gamma) and beta-catenin pathways have been involved in the pathogenesis of DN. Herein, we asked whether miR-27a mediates podocyte injury through PPAR gamma/beta-catenin signaling in DN. The functional relevance of miR-27a, PPAR gamma and beta-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 PPAR gamma, activated beta-catenin signaling as evidenced by upregulation of beta-catenin target genes, snail1 and a-smooth muscle actin (a-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 PPAR gamma/beta-catenin signaling were verified in renal biopsy samples from DN patients. We propose a novel role of the miR-27a/PPAR gamma/beta-catenin axis in fostering the progression toward more deteriorated podocyte injury in DN. Targeting miR-27a could be a potential therapeutic approach for DN
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