title: Forced expression of laminin beta1 in podocytes prevents nephrotic syndrome in mice lacking laminin beta2, a model for Pierson syndrome.
abstract: Pierson syndrome is a congenital nephrotic syndrome with ocular and neurological defects caused by mutations in LAMB2, the gene encoding the basement membrane protein laminin β2 (Lamβ2). It is the kidney glomerular basement membrane (GBM) that is defective in Pierson syndrome, as Lamβ2 is a component of laminin-521 (LM-521; α5β2γ1), the major laminin in the mature GBM. In both Pierson syndrome and the Lamb2(-/-) mouse model for this disease, laminin β1 (Lamβ1), a structurally similar homolog of Lamβ2, is marginally increased in the GBM, but it fails to fully compensate for the loss of Lamβ2, leading to the filtration barrier defects and nephrotic syndrome. Here we generated several lines of Lamβ1 transgenic mice and used them to show that podocyte-specific Lamβ1 expression in Lamb2(-/-) mice abrogates the development of nephrotic syndrome, correlating with a greatly extended lifespan. In addition, the more Lamβ1 was expressed, the less urinary albumin was excreted. Transgenic Lamβ1 expression increased the level of Lamα5 in the GBM of rescued mice, consistent with the desired increased deposition of laminin-511 (α5β1γ1) trimers. Ultrastructural analysis revealed occasional knob-like subepithelial GBM thickening but intact podocyte foot processes in aged rescued mice. These results suggest the possibility that up-regulation of LAMB1 in podocytes, should it become achievable, would likely lessen the severity of nephrotic syndrome in patients carrying LAMB2 mutations.
authors.affiliation: Renal Division, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Suh
authors.forename: George
authors.initials: G
authors.lastname: Jarad
authors.forename: Rene G
authors.initials: RG
authors.lastname: VanDeVoorde
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
mesh_terms: D000015:Abnormalities, Multiple / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000473:pathology* / Q000503:physiopathology; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005919:Glomerular Filtration Rate; D006801:Humans; D007223:Infant; D007797:Laminin / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020294:Myasthenic Syndromes, Congenital; D009404:Nephrotic Syndrome / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011681:Pupil Disorders / Q000473:pathology* / Q000503:physiopathology; D016019:Survival Analysis; D013997:Time Factors
chemical_list: C513277:Lamb1 protein, mouse; D007797:Laminin; C097043:laminin alpha5; C058783:laminin beta2