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 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.
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Min
M
Zhao
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Ying
Y
Chen
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Guixia
G
Ding
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Ying
Y
Xu
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Mi
M
Bai
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Yue
Y
Zhang
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Zhanjun
Z
Jia
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Songming
S
Huang
Department of Nephrology, Nanjing Children's Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
Aihua
A
Zhang
D000818:Animals; D002478:Cells, Cultured; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
C477819:15-deoxyprostaglandin J2; D047495:PPAR gamma; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D015230:Prostaglandin D2
PPAR-γ; Pathology Section; TGF-β1; epithelial cell phenotype; fibrosis; renal epithelial cells