期刊
ONCOTARGET
卷 7, 期 40, 页码 64690-64701出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11811
关键词
PPAR-gamma; TGF-beta 1; renal epithelial cells; epithelial cell phenotype; fibrosis; Pathology Section
资金
- National Natural Science Foundation of China [81530023, 81370802, 81300591, 81325004, 81270797]
- Natural Science Foundation of Jiangsu Province [BK20141079, BL2014007]
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.
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