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α3 Integrin of Cell-Cell Contact Mediates Kidney Fibrosis by Integrin-Linked Kinase in Proximal Tubular E-Cadherin Deficient Mice
- Source :
- American Journal of Pathology; July 2016, Vol. 186 Issue: 7 p1847-1860, 14p
- Publication Year :
- 2016
-
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.
Details
- Language :
- English
- ISSN :
- 00029440
- Volume :
- 186
- Issue :
- 7
- Database :
- Supplemental Index
- Journal :
- American Journal of Pathology
- Publication Type :
- Periodical
- Accession number :
- ejs38717416
- Full Text :
- https://doi.org/10.1016/j.ajpath.2016.03.015