Oncotarget

Research Papers: Pathology:

Renal tubular epithelium-targeted peroxisome proliferator-activated receptor-γ maintains the epithelial phenotype and antagonizes renal fibrogenesis

Min Zhao, Ying Chen, Guixia Ding, Ying Xu, Mi Bai, Yue Zhang, Zhanjun Jia, Songming Huang and Aihua Zhang _

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Oncotarget. 2016; 7:64690-64701. https://doi.org/10.18632/oncotarget.11811

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Abstract

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

Correspondence to:

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

Abstract

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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