Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis

Yi-Chun Yeh, Wei-Chun Wei, Yang-Kao Wang, Shih-Chieh Lin, Junne-Ming Sung, Ming-Jer Tang
American Journal of Pathology 2010, 177 (4): 1743-54
Transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-β1 enhances β(1) integrin levels in NMuMG cells, the detailed molecular mechanisms underlying TGF-β1-induced β(1) integrin gene expression and the role of β(1) integrin during EMT in the renal system are still unclear. In this study, we examined the role of β(1) integrin in TGF-β1-induced EMT both in vitro and in vivo. TGF-β1-induced augmentation of β(1) integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-β1-induced augmentation of β(1) integrin. TGF-β1 triggered β(1) integrin gene promoter activity as assessed by luciferase activity assay. Both knockdown of Smad3 and mutation of the Smad-binding element to block binding to the β(1) integrin promoter markedly reduced TGF-β1-induced β(1) integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-β1 enhanced Smad3 binding to the β(1) integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of β(1) integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of β(1) integrin and α-smooth muscle actin in tubule epithelia. Blockade of β(1) integrin signaling dampened the progression of fibrosis. Taken together, β(1) integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of β(1) integrin is a possible therapeutic target for prevention of renal fibrosis.

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