Transforming Growth Factor-β1 Induces Smad3-Dependent β1 Integrin Gene Expression in Epithelial-to-Mesenchymal Transition during Chronic Tubulointerstitial Fibrosis

Abstract

Transforming growth factor-␤1 (TGF-␤1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-␤1 enhances ␤ 1 integrin levels in NMuMG cells , the detailed molecular mechanisms underlying TGF-␤1-induced ␤ 1 integrin gene expression and the role of ␤ 1 integrin during EMT in the renal system are still unclear. In this study , we examined the role of ␤ 1 integrin in TGF-␤1-induced EMT both in vitro and in vivo. TGF-␤1-induced augmentation of ␤ 1 integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-␤1-induced augmentation of ␤ 1 integrin. TGF-␤1 triggered ␤ 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 ␤ 1 integrin promoter markedly reduced TGF-␤1-induced ␤ 1 integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-␤1 enhanced Smad3 binding to the ␤ 1 integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of ␤ 1 integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of ␤ 1 integrin and ␣-smooth muscle actin in tubule epithelia. Blockade of ␤ 1 integrin signaling dampened the progression of fibrosis. Taken together, ␤ 1 integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of ␤ 1 integrin is a possible therapeutic target for prevention of renal fibrosis.

Ulinastatin attenuates renal interstitial inflammation and inhibits fibrosis progression in rats under unilateral ureteral obstruction

“…Currently, TGF-β1 is recognized as one of the key factors in the formation and progression of interstitial fibrosis. It may induce renal tubular epithelial cell apoptosis, transdifferentiation of tubular epithelial cells into myofibroblasts (MFB), as well as excessive concentration of the ECM proteins, and eventually lead to interstitial fibrosis (24)(25)(26). The present study observed a significant increase in TGF-β1, Col-I and α-SMA expression levels in nephridial tissue, as well as interstitial fibrosis in the UUO group of rats.…”

β1 integrin is a crucial regulator of pancreatic β-cell expansion

“…Conversely, acinar cells, which we find to express low levels of β1 integrin, are unable to undergo significant proliferation unless they enter an acinar-to-ductal transdifferentiation (Fukuda et al, 2012;Kopp et al, 2012;Reichert et al, 2013). Islet cells have been reported to undergo epithelial-tomesenchymal transition when replicating (Kaido et al, 2010;Montgomery and Yebra, 2011), a phenomenon that has been described in many epithelial cell types and that is associated with significant upregulation of β1 integrin (Lim and Thiery, 2012;Yeh et al, 2010). This provides a possible mechanism by which cells about to enter the cell cycle can enhance their propensity to use this integrin subunit to respond to microenvironmental cues and activate pro-proliferative signaling cascades.…”

TGFβ modulates cell-to-cell communication in early epithelial-to-mesenchymal transition

“…Recent studies in cells from the proximal tubule have demonstrated that angiotensin II-induced tubular EMT was SMAD3-dependent [44]. Similarly, (β)1-integrin gene expression, a potential therapeutic target for renal fibrosis, is also upregulated in unilateral obstruction and in chronic tubulointerstitial fibrosis via a SMAD3-dependent mechanism [45]. However, despite the predominant involvement of SMAD3, a role for SMAD2 should not be discounted [46].…”