Alport syndrome is a genetic disorder resulting from mutations in type IV collagen genes. The defect results in pathological changes in kidney glomerular and inner-ear basement membranes. In the kidney, progressive glomerulonephritis culminates in tubulointerstitial fibrosis and death. Using gene knockout-mouse models, we demonstrate that two different pathways, one mediated by transforming growth factor (TGF)-β1 and the other by integrin α1β1, affect Alport glomerular pathogenesis in distinct ways. In Alport mice that are also null for integrin α1 expression, expansion of the mesangial matrix and podocyte foot process effacement are attenuated. The novel observation of normative laminin isoforms (laminin-2 and/or laminin-4) accumulating in the glomerular basement membrane of Alport mice is markedly reduced in the double knockouts. The second pathway, mediated by TGF-β1, was blocked using a soluble fusion protein comprising the extracellular domain of the TGF-β1 type II receptor. This inhibitor prevents focal thickening of the glomerular basement membrane, but does not prevent effacement of the podocyte foot processes. If both integrin α1β1 and TGF-β1 pathways are functionally inhibited, glomerular foot process and glomerular basement membrane morphology are primarily restored and renal function is markedly improved. These data suggest that integrin α1β1 and TGF-β1 may provide useful targets for a dual therapy aimed at slowing disease progression in Alport glomerulonephritis.
ASJC Scopus subject areas
- Pathology and Forensic Medicine