The global epidemic of chronic kidney disease is progressing at an alarming rate. In the United States alone, glomerular kidney diseases affect some 20 million people, and this number has roughly doubled in the last two decades. Indeed, kidney-related diseases are rapidly eluding present treatment options and resources. Thus, it is high priority to uncover novel therapeutics to treat chronic kidney diseases. Podocytes are specialized cells within the glomerulus that are essential for kidney ultrafiltration. They form foot processes (FPs), highly dynamic actin-based cellular extensions that are connected by slit diaphragms. Most forms of proteinuria and nephrotic syndrome are characterized by transformation of podocyte FPs into a band of cytoplasm due to de- regulation of the actin cytoskeleton (referred to as FP effacement). The work in this proposal is based on our recent identification of the GTPase dynamin as a major regulator of actin dynamics in podocytes. Studies from this laboratory suggest that preservation of dynamin function is sufficient to reverse FP effacement, restore functional podocytes and ameliorate proteinuria. We have recently shown that dynamin directly regulates the actin cytoskeleton in podocytes. In addition, we have identified small molecules that promote dynamin oligomerization into rings, which in turn protects actin cytoskeleton in podocytes. In this grant application we test the ability of dynamin ring stabilizer drugs to reverse FP effacement and ameliorate proteinuria in different rodent models of proteinuric kidney disease.
In Specific Aim 1 we test efficacy of dynamin drugs in inducible models of proteinuric kidney disease such as a rat model of puromycin aminonucleoside (PAN) nephrosis and a rat model of adriamycin nephrosis.
In Specific Aim 2 we test efficacy of dynamin ring stabilizer drugs in genetic models of proteinuric kidney diseases such as (1) mouse model in which actin cytoskeleton is mis- regulated due to expression of 'gain of function'1-actinin 4 mutant;(2) mice lacking CD2AP (adaptor protein involved in regulation of actin cytoskeleton and signaling in podocytes);(3) transgenic mice expressing high levels of TGF-?1.
In Specific Aim 3 we examine whether ring stabilizing drugs effect turnover of the nephrin at the plasma membrane. Our work has potential to identify dynamin drugs as novel therapeutics to treat proteinuric kidney diseases.
In the United States alone, glomerular type of kidney diseases effects some 20 million people, and this number has roughly doubled within the last two decades. Here we propose to test the ability of subset of small molecules (drugs) that specifically target GTPase dynamin to ameliorate proteinuria by restoring podocyte structure and function. Different drugs will be tested in inducible and genetic rodent models of proteinuric kidney diseases.
|Sever, Sanja; Schiffer, Mario (2018) Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases. Kidney Int 93:1298-1307|
|Schiffer, Mario; Teng, Beina; Gu, Changkyu et al. (2015) Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat Med 21:601-9|
|Reiser, Jochen; Sever, Sanja; Faul, Christian (2014) Signal transduction in podocytes--spotlight on receptor tyrosine kinases. Nat Rev Nephrol 10:104-15|
|Gu, Changkyu; Chang, Joann; Shchedrina, Valentina A et al. (2014) Regulation of dynamin oligomerization in cells: the role of dynamin-actin interactions and its GTPase activity. Traffic 15:819-38|
|Reiser, Jochen; Sever, Sanja (2013) Podocyte biology and pathogenesis of kidney disease. Annu Rev Med 64:357-66|
|Yaddanapudi, Suma; Altintas, Mehmet M; Kistler, Andreas D et al. (2011) CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest 121:3965-80|