Kindlin-2 mediates activation of TGF-β/Smad signaling and renal fibrosis

Abstract

Activation of TGF-b/Smad signaling plays a central role in the pathogenesis of tubulointerstitial fibrosis, but the mechanisms underlying the initial interaction of the TGF-b receptor with Smads, leading to their activation, remain unclear. Here, we found that Kindlin-2, an integrin-binding protein, physicallymediated the interaction of the TGF-b type I receptor (TbRI) with Smad3 in human kidney tubular epithelial cells. Kindlin-2 bound to TbRI through its FERMdomain and to Smad3 through itsNterminus. Overexpression of Kindlin-2 increased TGF-b-induced Smad3 activation. Knockdown of Kindlin-2 significantly suppressed the engagement of TbRI with Smad3 and inhibited TGF-b-induced Smad3 activation, as well as the expression of its target genes. Neither transfection of a Kindlin-2 mutant incapable of binding to b1 integrin nor knockdown of b1 integrin influenced the effect of Kindlin-2 on TGF-b1-induced Smad3 activation, indicating that this effect is independent of integrin. Kindlin-2 expression was markedly increased, predominantly in renal tubular epithelial cells, both in the unilateral ureteral obstruction model of kidney fibrosis and in human tissue exhibiting tubulointerstitial fibrosis. Furthermore, in the unilateral ureteral obstruction model, knocking down Kindlin-2 significantly inhibited activation of TGF-b/Smad signaling, decreased the expression of matrix genes, and ameliorated fibrosis. In summary, Kindlin-2 physically interacts with both TbRI and Smad3, promoting the activation of TGF-b/Smad signaling and contributing to the pathogenesis of tubulointerstitial fibrosis. Blockade of Kindlin-2 might be a rational therapeutic strategy for the treatment of fibrotic kidney diseases. Copyright © 2013 by the American Society of Nephrology.