α1β1 Integrin/Rac1-Dependent Mesangial Invasion of Glomerular Capillaries in Alport Syndrome

Alport syndrome, hereditary glomerulonephritis with hearing Loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of Laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary Loops of both models as well as in human Alport glomeruli, as the Likely source of this Laminin. L-NAME salt-induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin alpha 1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin alpha 1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin alpha 2-deficient Alport mice show reduced mesangial process invasion, and cultured Laminin alpha 2-null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin alpha 1 beta 1-dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology.