Kindlin-2 Mediates Activation of TGF-β/Smad Signaling and... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Wei, Xiaofan*; Xia, Yang†; Li, Feng†; Tang, Yan†; Nie, Jing*; Liu, Youhua*; Zhou, Zhanmei*; Zhang, Hongquan†; Hou, Fan Fan*

*Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China; and

†Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of China, and Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, China

Correspondence: Dr. Fan Fan Hou, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, P.R. China, or Dr. Hongquan Zhang, Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, #38 Xue Yuan Road, Beijing 100191, China. Email: [email protected] or [email protected]

Received October 31, 2012

Accepted March 28, 2013

Abstract

Activation of TGF-β/Smad signaling plays a central role in the pathogenesis of tubulointerstitial fibrosis, but the mechanisms underlying the initial interaction of the TGF-β receptor with Smads, leading to their activation, remain unclear. Here, we found that Kindlin-2, an integrin-binding protein, physically mediated the interaction of the TGF-β type I receptor (TβRI) with Smad3 in human kidney tubular epithelial cells. Kindlin-2 bound to TβRI through its FERM domain and to Smad3 through its N terminus. Overexpression of Kindlin-2 increased TGF-β–induced Smad3 activation. Knockdown of Kindlin-2 significantly suppressed the engagement of TβRI with Smad3 and inhibited TGF-β–induced Smad3 activation, as well as the expression of its target genes. Neither transfection of a Kindlin-2 mutant incapable of binding to β1 integrin nor knockdown of β1 integrin influenced the effect of Kindlin-2 on TGF-β1–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-β/Smad signaling, decreased the expression of matrix genes, and ameliorated fibrosis. In summary, Kindlin-2 physically interacts with both TβRI and Smad3, promoting the activation of TGF-β/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.