title: Kindlin-2 mediates activation of TGF-β/Smad signaling and renal fibrosis.
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.
authors.affiliation: Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Wei
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhanmei
authors.initials: Z
authors.lastname: Zhou
authors.forename: Hongquan
authors.initials: H
authors.lastname: Zhang
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology*; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009124:Muscle Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014517:Ureteral Obstruction / Q000473:pathology / Q000503:physiopathology
chemical_list: D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; D019012:Integrin beta1; D008565:Membrane Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C527802:kindlin-2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I