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 a 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 fot processes (FPs), highly dynamic actin-based cellular extensions that are connected by slit diaphragms. Most forms of proteinuria and nephrotic syndromes are characterized by the transformation of podocyte FPs into bands of cytoplasm due to dysregulation 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 shown that dynamin directly regulates the actin cytoskeleton in podocytes. In addition, we have identified small molecule that promotes dynamin oligomerization into rings, which in turn protects the actin cytoskeleton in podocytes. We have recently shown that administration of dynamin-specific small molecule reversed FP effacement and ameliorated proteinuria in diverse animal models of chronic kidney diseases. Originally, we focused on the role of dynamin in regulating the actin cytoskeleton in podocytes. In this grant application we expand our original observation by focusing on the role that dynamin-actin interaction, dynamin oligomerization, and dynamin-specific molecules play in regulating clathrin-mediated endocytosis. Endocytosis is a key process in all eukaryotes by which portions of the plasma membrane, along with extracellular material, are internalized. It plays an essential role in regulating signaling pathwas that originate at the plasma membrane.
In Specific Aim 1 we investigate the role that dynamin plays in regulating actin-dependent endocytosis in podocytes.
In Specific Aim 2 we investigate whether endocytosis plays a role during crosstalk between podocytes and glomerular endothelial cells.
In Specific Aim 3 we investigate whether actin-dependent endocytosis plays a role in reversing early signs of glomerular injury such as mesangial matrix expansion and deposition of collagen IV by examining the effects of dynamin-specific small molecules in rodent models of progressive kidney injury.

Public Health Relevance

In the United States alone, glomerular kidney diseases affects some 20 million people, and this number has roughly doubled within the last two decades. We have recently shown that a small molecule (drug) that specifically targets the GTPase dynamin restored podocyte structure and function and thus ameliorated proteinuria in diverse animal models of chronic kidney diseases. While we originally focused on the effects of this small molecule on the global organization of the actin cytoskeleton, here we propose to study its effects on actin-dependent clathrin-mediated endocytosis in podocytes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Sadusky, Anna Burkart
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Massachusetts General Hospital
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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