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

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. (PPAR-gamma) 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-gamma in protection of the epithelial phenotype and the antagonism of renal fibrosis and to define the underlying mechanisms. In response to TGF-beta 1 challenge, PPAR-gamma 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 alpha-SMA, indicating a loss of the epithelial phenotype. Oxidative stress induced by TGF-beta 1 was shown to be attributed to the alteration of the epithelial phenotype and PPAR-gamma inhibition. Activation of PPAR-gamma by its agonists of rosiglitazone and 15d-PGJ2 or genetic overexpression of PPAR-gamma prevented the loss of the epithelial phenotype induced by TGF-beta 1 in line with the inhibition of oxidative stress. To explore the role of PPAR-gamma in renal tubular epithelial in antagonizing fibrogenesis, PPAR-gamma was specifically deleted from RPTECs in mice. Following unilateral ureteral obstruction, the fibrosis was markedly deteriorated in mice with PPAR-gamma invalidation in RPTECs. Treatment with rosiglitazone attenuated tubulointerstitial fibrosis and epithelial phenotype transition in WT but not proximal tubule PPAR-gamma KO mice. Taken together, these findings identified an important role of renal tubular epithelium-targeted PPAR-gamma in maintaining the normal epithelial phenotype and opposing fibrogenesis, possibly via antagonizing oxidative stress.