Glomerular scarring is a hallmark of progressive kidney disease. Identifying molecular mechanisms of rare, familial kidney diseases has provided insights into the pathogenesis of sporadic nephropathy. Mutations in genes encoding podocyte proteins, which comprise the filtration barrier or regulate podocyte phenotype, have been discovered by genetic analyses of families with glomerulosclerosis, suggesting a podocyte phenotype """"""""switch"""""""" is a critical mechanism of glomerular scarring. We postulated that regulatory pathways transmit information from filtration barrier to nucleus to regulate podocyte differentiation state in response to environmental signals. WT1, a zinc finger transcription factor, critical for appropriate podocyte differentiation, expressed in mature podocytes and is mutated in familial glomerulosclerosis. WT1 expression is diminished in some human and experimental glomerular diseases, but podocyte expression of WT1 target genes, podocalyxin and nephrin, is diminished even when WT1 levels are unchanged. Using a two-hybrid assay to identify regulators of WT1 activity in a mouse kidney library, we identified a novel protein, WT1 interacting protein (WTIP). WTIP maps within a locus for familial focal sclerosis (FSGS1) on human chromosome 19q13.1 and is part of a family of zyxin-like molecules, which contain 3 LIM domains and shuttle between cytoplasm and nucleus. Our preliminary data demonstrated that WTIP is expressed in podocytes in culture and in vivo. Ectopically expressed WTIP co-localized with CD2-associated protein (CD2AP) in podocyte actin spots, sites of dynamic actin filament reorganization. Full-length WTIP, in the presence of the nuclear export inhibitor leptomycin, was retained in the nucleus, co-localized and coprecipitated with WT1, and inhibited WTl-dependent transcriptional activation of the amphiregulin promoter. Based on these data, we hypothesize the following: (1) In normal glomeruli WTIP is part of a multiprotein complex in podocyte foot process and may link the CD2AP/nephrin/podocin complex to adherens junction proteins by regulating dynamic actin assembly. (2) After injury, WTIP translocates into the nucleus, where it represses WTl-dependent gene expression to dysregulate podocyte phenotype. (3) Loss of WTIP from its cytosolic location also promotes redistribution of slit diaphragm proteins and actin rearrangement characteristic of foot process effacement. In vitro and in vivo experiments will test the validity of our model.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Pathology A Study Section (PTHA)
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Flessner, Michael Francis
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Case Western Reserve University
Internal Medicine/Medicine
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Kim, Jane H; Mukherjee, Amitava; Madhavan, Sethu M et al. (2012) WT1-interacting protein (Wtip) regulates podocyte phenotype by cell-cell and cell-matrix contact reorganization. Am J Physiol Renal Physiol 302:F103-15
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Keller, Benjamin; Martini, Sebastian; Sedor, John et al. (2010) Linking variants from genome-wide association analysis to function via transcriptional network analysis. Semin Nephrol 30:177-84
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