Integrin alpha1beta1 and transforming growth factor-beta1 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 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)-beta1 and the other by integrin alpha1beta1, 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 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-beta1, was blocked using a soluble fusion protein comprising the extracellular domain of the TGF-beta1 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 alpha1beta1 and TGF-beta1 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 alpha1beta1 and TGF-beta1 may provide useful targets for a dual therapy aimed at slowing disease progression in Alport glomerulonephritis.
Cosgrove
D
D
Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska, USA. cosgrove@boystown.org
Rodgers
K
K
Meehan
D
D
Miller
C
C
Bovard
K
K
Gilroy
A
A
Gardner
H
H
Kotelianski
V
V
Gotwals
P
P
Amatucci
A
A
Kalluri
R
R
D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D018450:Disease Progression; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D039222:Integrin alpha1beta1; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D009394:Nephritis, Hereditary / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D007141:Immunoglobulin Fc Fragments; D039222:Integrin alpha1beta1; D016023:Integrins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1