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1ß1 and Transforming Growth Factor-ß1 Play Distinct Roles in Alport Glomerular Pathogenesis and Serve as Dual Targets for Metabolic Therapy
From the Department of Genetics,*
Boys Town National
Research Hospital, Omaha, Nebraska; the Biogen
Corporation,
Cambridge, Massachusetts; the
Nephrology Division,
Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Massachusetts; and the
Scripps Institute,§
La Jolla, California
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)-ß1 and the other by
integrin 
1ß1, affect Alport glomerular pathogenesis in
distinct ways. In Alport mice that are also null for integrin 1
expression, expansion of the mesangial matrix and podocyte foot
process effacement are attenuated. The novel observation of nonnative
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-ß1, was blocked using a soluble fusion protein comprising
the extracellular domain of the TGF-ß1 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 1ß1 and TGF-ß1 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 1ß1 and
TGF-ß1 may provide useful targets for a dual therapy aimed at slowing
disease progression in Alport glomerulonephritis.
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