Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 186, Issue 7, Pages 1847-1860Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.03.015
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Funding
- National Health and Medical Research Council (NHMRC) of Australia [632688, 1026232]
- NHMRC Peter Doherty Fellowship
- University of Sydney New Staff/Early Career Researcher grant
- NHMRC [1003100]
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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. alpha 3 beta 1 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 alpha 3 beta 1 integrin at cell-cell adhesion. E-cadherin deficient proximal tubular epithelial cell displayed enhanced transforming growth factor-beta 1 induced alpha-smooth muscle actin (alpha-SMA) and vimentin expression, which was suppressed by siRNA silencing of alpha 3 integrin, but not beta 1 integrin. Up-regulation of transforming growth factor-beta 1 induced alpha-SMA was mediated by an a3 integrin-dependent increase in integrin-linked kinase (ILK). Src phosphorylation of beta-catenin and consequent p-beta-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 alpha 3 integrin-dependent increase of ILK, beta-catenin nuclear translocation, and alpha-SMA/proximal tubular specific Cre double positive staining in proximal tubular epithelial cell. These studies delineate a nonconventional integrin/ILK signaling by alpha 3 integrin dependent Src/p-beta-catenin-Y654/p-Smad2 mediated up-regulation of ILK through which loss of E-cadherin Leads to kidney fibrosis.
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