Integrin alpha 1 beta 1 and transforming growth factor-beta 1 play distinct roles in Alport glomerular pathogenesis and serve as dual targets for metabolic therapy

Alport syndrome is a genetic disorder resulting from mutations in type IV c ollagen genes. The defect results in pathological changes in kidney glomeru lar and inner-ear basement membranes. In the kidney, progressive glomerulon ephritis culminates in tubulointerstitial fibrosis and death. Using gene kn ockout-mouse models, we demonstrate that two different pathways, one mediat ed by transforming growth factor (TGF)-beta1 and the other by integrin alph a1 beta1, affect Alport glomerular pathogenesis in distinct ways. In Alport mice that are also null, for integrin alpha1 expression, expansion of the mesangial matrix and podocyte foot process effacement are attenuated. The n ovel observation of nonnative laminin isoforms (laminin-2 and/or laminin-3) accumulating in the glomerular basement membrane of Alport mice is markedl y reduced in the double knockouts. The second pathway, mediated by TGF-beta 1, was blocked using a soluble fusion protein comprising the extracellular domain of the TGF-beta1 type II receptor. This inhibitor prevents focal thi ckening of the glomerular basement membrane, but does not prevent effacemen t of the podocyte foot processes. If both Integrin alpha1 beta1 and TGF-bet a1 pathways are functionally inhibited, glomerular foot process and glomeru lar basement membrane morphology are primarily restored and renal function is markedly improved. These data suggest that integrin alpha1 beta1 and TGF -beta1 may provide useful targets for a dual therapy aimed at slowing disea se progression in Alport glomerulonephritis.