Laminin-1 reexpression in Alport mouse glomerular basement membranes.
BACKGROUND
Alport disease is a heritable basement membrane disorder caused by mutations in genes encoding the alpha3, alpha4, or alpha5 chains of type IV collagen, which normally comprise the collagenous network of mature glomerular basement membranes (GBMs). In Alport disease, the alpha3(IV), alpha4(IV), alpha5(IV) collagen network is absent and substituted for by alpha1(IV), and alpha2(IV) collagen, which normally is present only in developing, immature GBMs. The disease is marked by progressive GBM thickening and delamination, proteinuria, and renal failure. In addition to collagen IV dysregulation, abnormal GBM laminins also occur and may contribute to the pathogenesis of Alport glomerulopathy.


METHODS
To investigate laminin dysregulation in a mouse model of Alport disease, we used antibodies specific for laminin-alpha1 and -beta1 chains (to recognize laminin-1), and -alpha5 chain (to recognize laminin-11), and evaluated their distribution during glomerular development in alpha3(IV) collagen-deficient mice.


RESULTS
Developing glomeruli of infant alpha3(IV) collagen knockout mice underwent normal down-regulation of laminin-1, but laminin-1 chains were then reexpressed in maturing glomeruli, becoming concentrated in the subepithelial GBM projections typical of Alport disease. Immunoelectron microscopy showed that laminin-1 reexpression took place in both glomerular endothelial cells and podocytes.


CONCLUSIONS
The absence of a alpha3(IV), alpha4(IV), alpha5(IV) network may stimulate reexpression of laminin-1 by Alport mouse endothelial cells and podocytes. This abnormal GBM, which is more characteristic of immature glomeruli, may promote podocyte foot process effacement and reversion to a less differentiated state.
Abrahamson
Dale R
DR
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. dabrahamson@kumc.eduxu
Prettyman
A Corinne
AC
Robert
Barry
B
St  John
Patricia L
PL
D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001485:Basement Membrane / Q000378:metabolism / Q000503:physiopathology; D024141:Collagen Type IV / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology; D015870:Gene Expression; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000503:physiopathology*; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009394:Nephritis, Hereditary / Q000378:metabolism* / Q000503:physiopathology*
D001324:Autoantigens; D024141:Collagen Type IV; C478221:LAMB1 protein, human; C513277:Lamb1 protein, mouse; D007797:Laminin; C097043:laminin alpha5; C057112:type IV collagen alpha3 chain; C084098:laminin A