rosiglitazone inhibits transforming growth factor-β1 mediated fibrogenesis in adpkd cyst-lining epithelial cells罗格列酮抑制转化生长factor-β1介导纤维发生在adpkd cyst-lining上皮细胞.pdfVIP

Rosiglitazone Inhibits Transforming Growth Factor-b1 Mediated Fibrogenesis in ADPKD Cyst-Lining Epithelial Cells Yawei Liu., Bing Dai., Chenggang Xu., Lili Fu, Zhenhao Hua, Changlin Mei* Division of Nephrology, Nephrology Institute of PLA, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China Abstract Background: Interstitial fibrosis plays an important role in progressive renal dysfunction in autosomal dominant polycystic kidney disease (ADPKD). In our previous studies, we confirmed that PPAR-c agonist, rosiglitazone could protect renal function and prolong the survival of a slowly progressive ADPKD animal model by reducing renal fibrosis. However, the mechanism remains unknown. Methods: Primary culture epithelial cells pretreated with TGF-b1 were incubated with rosiglitazone. Extracellular matrix proteins were detected using real-time PCR and Western blotting. MAPK and Smad2 phosphorylation were measured with western blot. ERK1/2 pathway and P38 pathway were inhibited with the specific inhibitors PD98059 and SB203580. The Smad2 pathway was blocked with the siRNA. To address whether PPAR-c agonist-mediated inhibition of TGF-b1–induced collagen type I expression was mediated through a PPAR-c dependent mechanism, genetic and pharmaceutical approaches were used to block the activity of endogenous PPARc. Results: TGF- b1-stimulated collagen type I and fibronectin expression of ADPKD cyst-lining epithelia were inhibited by rosiglitazone in a dosage-dependent manner. Smad2, ERK1/2 and P38 pathways were activated in response to TGF-b1; however, TGF-b1 had little effect on JNK pathway. Rosiglitazone suppressed TGF-b1 induced Smad2 activation, while ERK1/2 and P38MAPK signals remained unaffected. Rosiglitazone could also attenuate TGF-b1-stimulated collagen type I and fibronectin