Research Papers: Pathology:
Renal tubular epithelium-targeted peroxisome proliferator-activated receptor-γ maintains the epithelial phenotype and antagonizes renal fibrogenesis
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Min Zhao1,2,*, Ying Chen1,2,*, Guixia Ding1,2, Ying Xu1,2, Mi Bai1,2, Yue Zhang1,2, Zhanjun Jia1,2, Songming Huang1,2 and Aihua Zhang1,2
1 Department of Nephrology, Nanjing Children’s Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
2 Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
* These authors have contributed equally to this work
Aihua Zhang, email:
Keywords: PPAR-γ, TGF-β1, renal epithelial cells, epithelial cell phenotype, fibrosis, Pathology Section
Received: February 19, 2016 Accepted: July 18, 2016 Published: September 01, 2016
Accumulating evidence suggests that loss of the renal tubular epithelial phenotype plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. Systemic activation of peroxisome proliferator-activated receptor γ (PPAR-γ) has been shown to be protective against renal fibrosis, although the mechanisms are poorly understood. The present study aimed to define the role of renal tubular epithelium-targeted PPAR-γ in protection of the epithelial phenotype and the antagonism of renal fibrosis and to define the underlying mechanisms. In response to TGF-β1 challenge, PPAR-γ expression and activity in the renal proximal tubule epithelial cells (RPTECs) were significantly reduced, and the reduction was accompanied by decreased E-cadherin and elevated α-SMA, indicating a loss of the epithelial phenotype. Oxidative stress induced by TGF-β1 was shown to be attributed to the alteration of the epithelial phenotype and PPAR-γ inhibition. Activation of PPAR-γ by its agonists of rosiglitazone and 15d-PGJ2 or genetic overexpression of PPAR-γ prevented the loss of the epithelial phenotype induced by TGF-β1 in line with the inhibition of oxidative stress. To explore the role of PPAR-γ in renal tubular epithelial in antagonizing fibrogenesis, PPAR-γ was specifically deleted from RPTECs in mice. Following unilateral ureteral obstruction, the fibrosis was markedly deteriorated in mice with PPAR-γ invalidation in RPTECs. Treatment with rosiglitazone attenuated tubulointerstitial fibrosis and epithelial phenotype transition in WT but not proximal tubule PPAR-γ KO mice. Taken together, these findings identified an important role of renal tubular epithelium-targeted PPAR-γ in maintaining the normal epithelial phenotype and opposing fibrogenesis, possibly via antagonizing oxidative stress.
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