Date of Award
Doctor of Philosophy (PhD)
The podocyte forms the outer layer of the filtration barrier in the glomerulus to prevent albumin leakage. Podocyte damage leads to focal segmental glomerulosclerosis (FSGS), a leading cause of chronic kidney disease. The cause of the majority of FSGS cases is unknown and referred to as sporadic FSGS. Genetic studies have identified genes as monogenic causes of FSGS in patients with a strong family history, but these cases account for only a small proportion of the FSGS population. Whether genetic susceptibility contributes to sporadic FSGS and which cellular process in the podocyte initiates the pathogenesis of FSGS are important questions that remain to be elucidated. To answer these questions, my research followed two different lines of inquiry. I performed a genetic analysis of both familial and sporadic FSGS patients, and I investigated the role of the actin cytoskeleton in podocytes. Based on expression analysis, we identified a new FSGS susceptibility gene, ARHGAP24, and showed that it was mutated in a family with FSGS. Since ARHGAP24 functions to maintain high Rho and low Rac levels, my work suggested that this balance might be important in FSGS. Using an inducible transgenic mouse model and multi-photon intravital microscopy, we validated that high activity of Rac1, one of the Rho family GTPases, is responsible for podocyte foot process effacement, increased membrane dynamics, and podocyte shedding into the urine, three important processes that lead to proteinuria and FSGS. By sequencing a large cohort of sporadic FSGS patients, I identified 16 potential FSGS susceptibility genes that were novel. Using a novel podocyte-specific indicible RNAi mouse model that I developed, four of these genes were validated. Some of these genes function as regulators of the actin cytoskeleton. Our genetic study further reinforces the role of actin cytoskeletal regulation in the pathogenesis of FSGS.
Chair and Committee
Andrey S Shaw
Jeffrey H Miner, Kendall J Blumer, Phyllis I Hanson, Gregory D Longmore, David M Ornitz
Yu, Haiyang, "Genetic and Cellular Studies of The Podocyte in Focal Segmental Glomerulosclerosis" (2015). Arts & Sciences Electronic Theses and Dissertations. 431.