| First Author | Zheng G | Year | 2016 |
| Journal | Am J Pathol | Volume | 186 |
| Issue | 7 | Pages | 1847-60 |
| PubMed ID | 27182643 | Mgi Jnum | J:234014 |
| Mgi Id | MGI:5788791 | Doi | 10.1016/j.ajpath.2016.03.015 |
| Citation | Zheng G, et al. (2016) alpha3 Integrin of Cell-Cell Contact Mediates Kidney Fibrosis by Integrin-Linked Kinase in Proximal Tubular E-Cadherin Deficient Mice. Am J Pathol 186(7):1847-60 |
| abstractText | 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. alpha3beta1 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 alpha3beta1 integrin at cell-cell adhesion. E-cadherin-deficient proximal tubular epithelial cell displayed enhanced transforming growth factor-beta1-induced alpha-smooth muscle actin (alpha-SMA) and vimentin expression, which was suppressed by siRNA silencing of alpha3 integrin, but not beta1 integrin. Up-regulation of transforming growth factor-beta1-induced alpha-SMA was mediated by an alpha3 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 alpha3 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 alpha3 integrin-dependent Src/p-beta-catenin-Y654/p-Smad2-mediated up-regulation of ILK through which loss of E-cadherin leads to kidney fibrosis. |
