Revealing New Therapeutic Opportunities for Kidney Glomerular Diseases by Elucidating the Mechanobiological Functions of Novel Cytoskeletal Structures in Podocytes

Project Summary Chronic kidney diseases, of which glomerular diseases form the most significant component, are quite common and estimated to affect from 5 to 11% of the population. Specific treatment options for various forms of chronic kidney disease in general are extremely limited, in part due to the poor understanding of

the pathogenesis of glomerular diseases. What has been apparent since the advent of electron microscopic visualization of the glomerular filtration barrier is that loss of typical podocyte foot process architecture, termed podocyte foot process effacement, is a hallmark of proteinuric glomerular diseases.

The overall goal of this research is to better understand the mechanisms that ensure podocyte homeostasis, the maintenance of normal podocyte architecture and adhesion to the glomerular basement membrane, and the pathogenic mechanisms that promote podocyte foot process effacement and the subsequent detachment. By better understanding these mechanisms, targeted therapies to

intervene in these pathways can be designed to improve the outcomes of patients either already living with or at risk of glomerular disease. Proof of concept therapeutic approaches are proposed in this project. The overall focus of this application involves several mechanistic aspects of podocyte cytoskeletal

dynamics in relation to slit diaphragm stability, foot process shape, and adhesion to the underlying GBM through integrins. Our hypothesis is that podocyte foot process adhesion dynamics can be controlled by modulating tensional homeostasis in cytoskeletal networks of both contractile and non-contractile actin cables that bind integrins and slit diaphragms. The Specific Aims are focused

on the functions of synaptopodin (Aim 1), CD2-associated protein (CD2AP; Aim 2), and integrin-based podocyte adhesion in health and disease states (Aim 3). We will investigate how these three aspects of podocyte biology cooperate and interact with each other to ensure podocyte homeostasis under the constant stress of filtration. We will use several novel, innovative approaches to carry out the Aims and

will use our mouse models of nephrotic syndrome and Alport syndrome as highly relevant human disease models. The results of the proposed experiments, which also have biochemical, mechanobiological, state of the art imaging, and primary podocyte cell culture components, will lead to an improved understanding of diverse aspects of podocyte biology and reveal clear pathways towards

the development of new therapies for patients.