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Developmental origins for kidney disease due to Shroom3 deficiency
Journal of the American Society of Nephrology
  • Hadiseh Khalili, McMaster University Medical Centre
  • Alexandra Sull, Western University
  • Sanjay Sarin, McMaster University Medical Centre
  • Felix J. Boivin, McMaster University Medical Centre
  • Rami Halabi, Western University
  • Bruno Svajger, McMaster University Medical Centre
  • Aihua Li, McMaster University Medical Centre
  • Valerie Wenche Cui, McMaster University Medical Centre
  • Thomas Drysdale, Western University
  • Darren Bridgewater, McMaster University Medical Centre
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CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroomfamilymember 3 (SHROOM3) gene, which encodes an actin-associated protein important in epithelial morphogenesis. However, the role of SHROOM3 in kidney development and function is virtually unknown. Studies in zebrafish and rat showed that alterations in Shroom3 can result in glomerular dysfunction. Furthermore, human SHROOM3 variants can induce impaired kidney function in animal models. Here, we examined the temporal and spatial expression of Shroom3 in the mammalian kidney. We detected Shroom3 expression in the condensing mesenchyme, Bowman's capsule, and developing and mature podocytes in mice. Shroom3 null (Shroom3Gt/Gt) mice showed marked glomerular abnormalities, including cystic and collapsing/degenerating glomeruli, and marked disruptions in podocyte arrangement and morphology. These podocyte-specific abnormalities are associated with altered Rho-kinase/myosin II signaling and loss of apically distributed actin. Additionally, Shroom3 heterozygous (Shroom3Gt/+) mice showed developmental irregularities that manifested as adult-onset glomerulosclerosis and proteinuria. Taken together, our results establish the significance of Shroom3 in mammalian kidney development and progression of kidney disease. Specifically, Shroom3 maintains normal podocyte architecture in mice via modulation of the actomyosin network, which is essential for podocyte function. Furthermore, our findings strongly support the GWASs that suggest a role for SHROOM3 in human kidney disease.

Citation Information
Hadiseh Khalili, Alexandra Sull, Sanjay Sarin, Felix J. Boivin, et al.. "Developmental origins for kidney disease due to Shroom3 deficiency" Journal of the American Society of Nephrology Vol. 27 Iss. 10 (2016) p. 2965 - 2973
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