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Developmental origins for kidney disease in Shroom3 deficient mice
Author(s) -
Bridgewater Darren,
Khalili Hadiseh,
Sull Alexandra,
Drysdale Thomas
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.84.3
Subject(s) - podocyte , kidney development , mesenchyme , biology , kidney , nephron , kidney disease , pathology , glomerular basement membrane , glomerulosclerosis , kidney glomerulus , glomerulonephritis , microbiology and biotechnology , endocrinology , embryonic stem cell , medicine , genetics , proteinuria , mesenchymal stem cell , gene
Background Numerous Genome Wide Association Studies (GWAS) have linked Shroom3 to chronic kidney disease and glomerular function. Shroom3, a cytoskeletal effector protein, regulates cell shape changes during embryogenesis. However, the role of Shroom3 in kidney function and nephron formation is not completely understood. We hypothesized that Shroom3 regulates podocyte cyto‐architecture. Results: Shroom3 is dynamically expressed in the condensing mesenchyme, podocyte cells, and collecting duct system during kidney development as shown by LacZ staining, affymetrix two‐plex in situ hybridization, and immuno‐histochemistry. Shroom3 expression was maintained in podocytes and collecting ducts in post‐natal kidneys. Histological analysis of embryonic kidneys from Shroom3‐/‐ and Shroom3+/‐ mice demonstrated cystic and collapsing glomeruli and a 1.7 and 1.4‐fold reduction in glomerular number respectively. By 1 year Shroom3+/‐ mice developed glomerulosclerosis and albuminuria. Electron microscopy analysis of Shroom3 ‐/‐ and Shroom3+/‐ glomeruli demonstrated reduced cellularity, mesangial expansion, abnormalities in the endothelial basement membrane, damage to the podocyte cell body, and sporadic podocyte foot process effacement. Conclusion The absence of Shroom3 leads to early defects in podocyte formation and cyto‐architecture. This causes glomerular abnormalities, reduced glomerular number, and postnatal glomerular disease. These results support the GWAS studies and demonstrate Shroom3 plays important role in kidney formation and kidney disease.