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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 ?2 (Lam?2). It is the kidney glomerular basement membrane (GBM) that is defective in Pierson syndrome, as Lam?2 is a component of laminin-521 (LM-521; ?5?2?1), the major laminin in the mature GBM. In both Pierson syndrome and the Lamb2(-/-) mouse model for this disease, laminin ?1 (Lam?1), a structurally similar homolog of Lam?2, is marginally increased in the GBM, but it fails to fully compensate for the loss of Lam?2, leading to the filtration barrier defects and nephrotic syndrome. Here we generated several lines of Lam?1 transgenic mice and used them to show that podocyte-specific Lam?1 expression in Lamb2(-/-) mice abrogates the development of nephrotic syndrome, correlating with a greatly extended lifespan. In addition, the more Lam?1 was expressed, the less urinary albumin was excreted. Transgenic Lam?1 expression increased the level of Lam?5 in the GBM of rescued mice, consistent with the desired increased deposition of laminin-511 (?5?1?1) 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.

SUBMITTER: Suh JH

PROVIDER: S-EPMC3174642 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Forced expression of laminin beta1 in podocytes prevents nephrotic syndrome in mice lacking laminin beta2, a model for Pierson syndrome.

Suh Jung Hee JH Jarad George G VanDeVoorde Rene G RG Miner Jeffrey H JH

Proceedings of the National Academy of Sciences of the United States of America 20110829 37

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 ...[more]

PMID: 21876163

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Project description:BackgroundNephrotic syndrome (NS) is a common renal disorder in children attributed to podocyte injury. However, children with the same diagnosis have markedly variable treatment responses, clinical courses, and outcomes, suggesting molecular heterogeneity.PurposeThis study aimed to explore the molecular responses of podocytes to nephrotic plasma to identify specific genes and signaling pathways differentiating various clinical NS groups as well as biological processes that drive injury in normal podocytes.MethodsTranscriptome profiles from immortalized human podocyte cell line exposed to the plasma of 8 subjects (steroidsensitive nephrotic syndrome [SSNS], n=4; steroid-resistant nephrotic syndrome [SRNS], n=2; and healthy adult individuals [control], n=2) were generated using microarray analysis.ResultsUnsupervised hierarchical clustering of global gene expression data was broadly correlated with the clinical classification of NS. Differential gene expression (DGE) analysis of diseased groups (SSNS or SRNS) versus healthy controls identified 105 genes (58 up-regulated, 47 down-regulated) in SSNS and 139 genes (78 up-regulated, 61 down-regulated) in SRNS with 55 common to SSNS and SRNS, while the rest were unique (50 in SSNS, 84 genes in SRNS). Pathway analysis of the significant (P≤0.05, -1≤ log2 FC ≥1) differentially expressed genes identified the transforming growth factor-β and Janus kinase-signal transducer and activator of transcription pathways to be involved in both SSNS and SRNS. DGE analysis of SSNS versus SRNS identified 2,350 genes with values of P≤0.05, and a heatmap of corresponding expression values of these genes in each subject showed clear differences in SSNS and SRNS.ConclusionOur study observations indicate that, although podocyte injury follows similar pathways in different clinical subgroups, the pathways are modulated differently as evidenced by the heatmap. Such transcriptome profiling with a larger cohort can stratify patients into intrinsic subtypes and provide insight into the molecular mechanisms of podocyte injury.

Dataset Information

Forced expression of laminin beta1 in podocytes prevents nephrotic syndrome in mice lacking laminin beta2, a model for Pierson syndrome.

Publications

Forced expression of laminin beta1 in podocytes prevents nephrotic syndrome in mice lacking laminin beta2, a model for Pierson syndrome.

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