Understanding Podocyte Biology to Develop Novel Kidney Therapeutics

Abstract

Over the past two decades it has become increasing clear that injury and loss of podocytes is an early and common clinical observation presented in many forms of glomerulopathy and chronic kidney disease. Identification of disease-causing monogenic mutations in numerous podocyte-expressed genes as well as studies conducted using preclinical animal models have shown that the podocyte plays a central role in establishing kidney dysfunction. In this review, we summarize current knowledge regarding the potential for podocyte-targeted therapies and give our view on how a deeper understanding of the molecular makeup of the podocyte will enable future therapeutic interventions. Specifically, we recount some of the currently described podocentric strategies for therapy and summarize the status and evolution of various model systems used to facilitate our understanding of the molecular and functional underpinnings of podocyte biology.

Keywords: chronic kidney disease; diabetic nephropathy; glomerulus; podocyte; targeted therapy.

Figures

Figure 1

Glomerular histopathology in DN. (A,B) Diabetic glomeruli present nodular expansion of mesangial matrix as detected by periodic acid-Schiff staining. (C,D) The number of podocytes is decreased in DN glomeruli as demonstrated by wt1 staining (marker for podocyte nuclei). Magnifications: ×200.

Figure 2

Glomerular pathology in Gprc5a-deficient mice. (A,B) Mesangial matrix is expanded in aging Gprc5a KO mice. (C,D) Electron microscopy reveals thickening of the GBM in Gprc5a-deficient mice, which is a hallmark sign of DN in humans. Magnifications: ×400 (A,B). Scale bars: 300 nm (C,D).

Figure 3

Model systems for podocyte drug discovery. The challenge of drug discovery and development lies in finding the balance between high throughput reductionist assay systems of limited physiological context and model systems with lower throughput but increasing physiological relevance and translation. Biochemical assays facilitate screening of a given drug target against a large library of compounds. Cellular context and target validation can be afforded using 2D podocyte cell culture and appropriate phenotypic readouts, such as actin cytoskeletal dynamics and apoptosis. Microphysiological systems that recapitulate the form and function of the glomerular filtration barrier, ex vivo glomeruli, kidney organoids and animal models from diverse species all lend increasing physiological complexity to target validation. As methodologies continue to evolve and improve in terms of their physiological context and throughput, there are increasing opportunities to accommodate these systems into a drug discovery cascade for identification of podocyte therapeutics.