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J Am Soc Nephrol. 2016 Oct;27(10):2965-2973. Epub 2016 Mar 3.

Developmental Origins for Kidney Disease Due to Shroom3 Deficiency.

Author information

1
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
2
Departments of Physiology and Pharmacology and.
3
Departments of Physiology and Pharmacology and Pediatrics, University of Western Ontario, London, Ontario, Canada; and tadrysda@uwo.ca Bridgew@mcmaster.ca.
4
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Center for Kidney Research, St. Josephs Healthcare, Hamilton, Ontario, Canada tadrysda@uwo.ca Bridgew@mcmaster.ca.

Abstract

CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroom family member 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.

KEYWORDS:

Shroom3; chronic kidney disease; kidney development; kidney disease; podocyte

PMID:
26940091
PMCID:
PMC5042660
DOI:
10.1681/ASN.2015060621
[Indexed for MEDLINE]
Free PMC Article

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