| First Author | Delimont D | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 6 | Pages | e99083 |
| PubMed ID | 24915008 | Mgi Jnum | J:218570 |
| Mgi Id | MGI:5617924 | Doi | 10.1371/journal.pone.0099083 |
| Citation | Delimont D, et al. (2014) Laminin alpha2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. PLoS One 9(6):e99083 |
| abstractText | It has been known for some time that laminins containing alpha1 and alpha2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM) of Alport mice, dogs, and humans. We show that laminins containing the alpha2 chain, but not those containing the alpha1 chain activates focal adhesion kinase (FAK) on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of alpha2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP-12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin alpha2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages. |
