title: Laminin alpha4-null mutant mice develop chronic kidney disease with persistent overexpression of platelet-derived growth factor.
abstract: Each extracellular matrix compartment in the kidney has a unique composition, with regional specificity in the expression of various laminin isoforms. Although null mutations in the majority of laminin chains lead to specific developmental abnormalities in the kidney, Lama4-/- mice have progressive glomerular and tubulointerstitial fibrosis. These mice have a significant increase in expression of platelet-derived growth factor (PDGF)-BB, PDGF-DD, and PDGF receptor beta in association with immature glomerular and peritubular capillaries. In addition, mesangial cell exposure to alpha4-containing laminins, but not other isoforms, results in down-regulation of PDGF receptor mRNA and protein, suggesting a direct effect of LN411/LN421 on vessel maturation. Given the known role of overexpression of PDGF-BB and PDGF-DD on glomerular and tubulointerstitial fibrosis, these data suggest that failure of laminin alpha4-mediated down-regulation of PDGF activity contributes to the progressive renal lesions in this animal model. Given the recent demonstration that individuals with laminin alpha4 mutations develop cardiomyopathy, these findings may be relevant to kidney disease in humans.
authors.affiliation: Primary and Specialty Care Medicine, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA. cabrass@u.washington.edu
authors.forename: Christine K
authors.initials: CK
authors.lastname: Abrass
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hansen
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Patton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008853:Microscopy / Q000379:methods; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000235:genetics
chemical_list: C501370:Lama4 protein, mouse; D007797:Laminin; D010982:Platelet-Derived Growth Factor; D021122:Protein Subunits