title: MicroRNA-27a promotes renal tubulointerstitial fibrosis via suppressing PPARγ pathway in diabetic nephropathy.
abstract: MicroRNA-27a (miR-27a) upregulation has been identified in diabetes, but the pathogenesis of miR-27a in renal tubulointerstitial fibrosis (TIF) in diabetic nephropathy (DN) has not been elucidated. Herein, we found that high glucose stimulated miR-27a expression, which directly inhibited PPARγ and promoted fibrosis in NRK-52E cells. The functional relevance of miR-27a-dependent PPARγ decrease was proven by inhibition or overexpression of miR-27a both in vitro and in streptozotocin-induced diabetic rats. MiR-27a, via repression of PPARγ, activates the TGF-β/Smad3 signaling and contributes to the expressional changes of connective tissue growth factor (CTGF), Fibronectin and Collagen I, key mediators of fibrosis. Furthermore, we provide evidences that plasma miR-27a upregulation contributed to unfavorable renal function and increased TIF in renal tissues of diabetic rats and DN patients. Notably, miR-27a exhibited clinical and biological relevance as it was linked to elevated serum creatinine, proteinuria, urinary N-acetyl-β-D-glucosaminidase (NAG), and reduced estimated glomerular filtration rate (eGFR). Thus, we propose a novel role of the miR-27a-PPARγ axis in fostering the progression toward more deteriorated renal TIF in DN. Monitoring plasma miR-27a level and its association with PPARγ can be used to reflect the severity of renal TIF. Targeting miR-27a could be evaluated as 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, PR China.|Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.|Department of Nephrology, The First Affiliated Hospital, Inner Mongolia Medical University, Hohhot, Inner Mongolia, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hou
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, PR China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Xun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
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, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D047495:PPAR gamma; D005947:Glucose
keywords: PPARγ; TGF-β/Smad3; diabetic nephropathy; miR-27a; renal tubulointerstitial fibrosis