title: MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy.
abstract: 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.
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Zhanmei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Wan
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, People's Republic of China.|Department of Nephrology, The First Affiliated Hospital, Inner Mongolia Medical University, Hohhot, Inner Mongolia, People's Republic of China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Bai
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000633:toxicity; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D047495:PPAR gamma; D051176:beta Catenin; D005947:Glucose