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Am J Pathol. 2016 Jul;186(7):1847-60. doi: 10.1016/j.ajpath.2016.03.015. Epub 2016 May 13.

α3 Integrin of Cell-Cell Contact Mediates Kidney Fibrosis by Integrin-Linked Kinase in Proximal Tubular E-Cadherin Deficient Mice.

Author information

  • 1Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia. Electronic address: guoping.zheng@sydney.edu.au.
  • 2Centre 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.
  • 3Centre 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.
  • 4Centre 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.
  • 5Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
  • 6Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Centenary Institute and Department of Dermatology, University of Sydney, Sydney, Australia.
  • 7Department of Respiratory Medicine, the Second Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
  • 8Embryology Unit, Children's Medical Research Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.
  • 9Laboratory of Molecular Physio-Medicine, National Centre for Scientific Research, University of Nice-Sophia Antipolis, Parc Valrose, Nice, France.
  • 10Centre for Kidney Research, Children's Hospital at Westmead, Sydney, Australia.

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.

PMID:
27182643
DOI:
10.1016/j.ajpath.2016.03.015
[PubMed - in process]
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