MicroRNA-27a promotes renal tubulointerstitial fibrosis via suppressing PPARγ pathway in diabetic nephropathy
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Xiaoyan Hou1,2,3, Jianwei Tian1, Jian Geng4, Xiao Li5, Xun Tang2, Jun Zhang2, Xiaoyan Bai1
1Division 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
2Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China
3Department of Nephrology, The First Affiliated Hospital, Inner Mongolia Medical University, Hohhot, Inner Mongolia, PR China
4Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China
5Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China
Jun Zhang, email: [email protected]
Keywords: miR-27a, PPARγ, TGF-β/Smad3, renal tubulointerstitial fibrosis, diabetic nephropathy
Received: January 27, 2016 Accepted: June 12, 2016 Published: June 24, 2016
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.
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