title: α3 Integrin of Cell-Cell Contact Mediates Kidney Fibrosis by Integrin-Linked Kinase in Proximal Tubular E-Cadherin Deficient Mice.
abstract: Loss of E-cadherin marks a defect in epithelial integrity and polarity during tissue injury and fibrosis. Whether loss of E-cadherin plays a causal role in fibrosis is uncertain. α3β1 Integrin has been identified to complex with E-cadherin in cell-cell adhesion, but little is known about the details of their cross talk. Herein, E-cadherin gene (Cdh1) was selectively deleted from proximal tubules of murine kidney by Sglt2Cre. Ablation of E-cadherin up-regulated α3β1 integrin at cell-cell adhesion. E-cadherin-deficient proximal tubular epithelial cell displayed enhanced transforming growth factor-β1-induced α-smooth muscle actin (α-SMA) and vimentin expression, which was suppressed by siRNA silencing of α3 integrin, but not β1 integrin. Up-regulation of transforming growth factor-β1-induced α-SMA was mediated by an α3 integrin-dependent increase in integrin-linked kinase (ILK). Src phosphorylation of β-catenin and consequent p-β-catenin-Y654/p-Smad2 transcriptional complex underlies the transcriptional up-regulation of ILK. Kidney fibrosis after unilateral ureteric obstruction or ischemia reperfusion was increased in proximal tubule E-cadherin-deficient mice in comparison to that of E-cadherin intact control mice. The exacerbation of fibrosis was explained by the α3 integrin-dependent increase of ILK, β-catenin nuclear translocation, and α-SMA/proximal tubular-specific Cre double positive staining in proximal tubular epithelial cell. These studies delineate a nonconventional integrin/ILK signaling by α3 integrin-dependent Src/p-β-catenin-Y654/p-Smad2-mediated up-regulation of ILK through which loss of E-cadherin leads to kidney fibrosis.
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia. Electronic address: guoping.zheng@sydney.edu.au.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia; Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia; Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia; Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia; Department of Respiratory Medicine, the First Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Pang
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia; Department of Renal Medicine, the Second Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: So R
authors.initials: SR
authors.lastname: Lee
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Tzu-Ting
authors.initials: TT
authors.lastname: Hsu
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Thian K
authors.initials: TK
authors.lastname: Tan
authors.affiliation: Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Centenary Institute and Department of Dermatology, University of Sydney, Sydney, Australia.
authors.forename: J Guy
authors.initials: JG
authors.lastname: Lyons
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Respiratory Medicine, the Second Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Tian
authors.affiliation: Embryology Unit, Children's Medical Research Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: David A F
authors.initials: DAF
authors.lastname: Loebel
authors.affiliation: Laboratory of Molecular Physio-Medicine, National Centre for Scientific Research, University of Nice-Sophia Antipolis, Parc Valrose, Nice, France.
authors.forename: Isabella
authors.initials: I
authors.lastname: Rubera
authors.affiliation: Laboratory of Molecular Physio-Medicine, National Centre for Scientific Research, University of Nice-Sophia Antipolis, Parc Valrose, Nice, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Yuan M
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Changqi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Vincent W S
authors.initials: VWS
authors.lastname: Lee
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.affiliation: Embryology Unit, Children's Medical Research Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Patrick P L
authors.initials: PPL
authors.lastname: Tam
authors.affiliation: Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: David C H
authors.initials: DCH
authors.lastname: Harris
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000172:deficiency*; D002448:Cell Adhesion; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000099200:Scaffold Protein ILK
chemical_list: D015820:Cadherins; D039201:Integrin alpha3beta1; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C000611838:Cdh1 protein, mouse