Developmental Origins for Kidney Disease Due to Shroom3 Deficiency

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 (Shroom3 Gt/+ ) 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.

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

“…76 The down-regulated genes included CGA, PSG1, and SHOOM3, which is essential for normal kidney development in mice. 77 We also found decreased expression of an mRNA that encodes ELOVL2, which is involved in the extension of long-chain fatty acids. In addition, the cell surface heparan sulfate proteoglycan, Glypican 3, was also expressed at lower levels.…”

The Susceptibility Genes in Diabetic Nephropathy

“…Shroom3 protein mainly regulates the morphogenesis of epithelial cells and tissues. In the rat kidney, the shroom3 protein is expressed in the condensing mesenchyme, Baumann’s sac, and podocytes [43]. Knockout of this gene can lead to significant abnormalities in the rat glomeruli, which are characterized by the collapse and degeneration of glomerular cysts and remarkable damage to the arrangement and morphology of podocytes.…”

“…Knockout of this gene can lead to significant abnormalities in the rat glomeruli, which are characterized by the collapse and degeneration of glomerular cysts and remarkable damage to the arrangement and morphology of podocytes. In short, it maintains the normal structure and function of podocytes by adjusting the actin mesh [43]. A GWAS found that the rs17319721 SNP in the intronic region of the SHROOM3 gene was associated with CKD [44].…”

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“…Activation of this Rock/MyoII signaling pathway causes localized contraction of actin-myosin networks at the apical surface of the podocyte, resulting in changes in cell morphology [51]. In addition, Shroom3 heterozygous (Shroom3Gt/+) mice showed developmental abnormalities that manifested as adult-onset glomerulosclerosis and proteinuria [52] (Table 2; Fig. 1).…”