Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Thomas Drysdale

Abstract

Chronic kidney disease (CKD) affects 10% of the population in industrialized nations. Recent genome wide association studies (GWAS) have correlated SHROOM3 with glomerular filtration rate and albuminuria. To elucidate Shroom3’s role in the kidney, I employed a gene trap mouse model (Shroom3Gt/Gt allele) that produces a non-functional Shroom3 protein. Shroom3 is expressed in the podocytes embryonically and in adulthood as well as other cell types. Shroom3 loss results in glomerular cysts and reduced glomerular number. Some Shroom3+/Gt and Shroom3Gt/Gt podocytes showed loss of apical ROCK1, pMLC and actin consistent with the role of Shroom3 in actin organization. Shroom3+/Gt also showed reduced glomerular number and cystic glomeruli and some adult Shroom3+/Gt have albuminuria, a sign of CKD. Therefore, Shroom3 is required for normal kidney development and reduced Shroom3 function can result in adult-onset kidney disease. This provides a mechanistic explanation for the GWAS studies in humans correlating SHROOM3 with CKD.


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