? End stage renal disease (ESRD) is an important public health issue. Based on 2005 USRDS data ESRD patients utilize 19.2 percent of medicare spending (21.3 billion dollars). Diabetic nephropathy and glomerulonephritis contributes about 56.5 percent of the incident patients on dialysis. Glomerulus is the filtering unit of the kidney. Podocytes are morphologically unique cells, which have octopus-like processes (foot processes) which interdigitate to form the slit diaphragm. Most glomerular diseases present with proteinuria and podocyte foot process effacement. Our lab has identified signaling mechanisms employed by slit diaphragm proteins to regulate the actin cytoskeleton of the podocyte. These signaling mechanisms appear to be essential for maintaining the unique structure and function of this cell. Human mutations of several of these gene products such as Nephrin, Podocin, and alpha actinin-4 lead to foot process effacement and proteinuria and result in scarring of the kidney causing renal failure and eventually end stage renal disease requiring dialysis. The guiding hypothesis of this application is that the slit diaphragm protein complex regulates podocyte actin cytoskeletal dynamics. Based on our preliminary work, this project will focus on several aspects of this mechanism. Specifically we will: (1) Investigate signaling mechanisms by which Nephrin and Neph1 cooperate in actin polymerization. Our preliminary data suggests a role for nWASP and cortactin in Nephrin/Neph1 mediated actin polymerization. These proteins are known to assemble, promote, regulate and stabilize the actin polymerization complex. Using biochemical and cell biological techniques we will characterize the interaction of these two proteins with Nephrin and Neph1. (2) Investigate the role of cofilin in podocyte actin cytoskeletal dynamics. Our preliminary data shows a signaling relationship between Nephrin and cofilin. Cofilin is necessary for actin polymerization and remodeling. 3. To further characterize the physiological role of cofilin in podocytes in development and in podocyte injury, we will engineer and phenotye mice deleted of cofilin in a podocyte-specific fashion. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Verma, Rakesh; Venkatareddy, Madhusudan; Kalinowski, Anne et al. (2016) Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury. Mol Cell Biol 36:596-614
Verma, Rakesh; Venkatareddy, Madhusudan; Kalinowski, Anne et al. (2016) Integrin Ligation Results in Nephrin Tyrosine Phosphorylation In Vitro. PLoS One 11:e0148906
George, Britta; Verma, Rakesh; Soofi, Abdulsalam A et al. (2012) Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest 122:674-92
Garg, Puneet; Holzman, Lawrence B (2012) Podocytes: gaining a foothold. Exp Cell Res 318:955-63
Venkatareddy, Madhusudan; Cook, Leslie; Abuarquob, Kamal et al. (2011) Nephrin regulates lamellipodia formation by assembling a protein complex that includes Ship2, filamin and lamellipodin. PLoS One 6:e28710
Garg, Puneet; Rabelink, Ton (2011) Glomerular proteinuria: a complex interplay between unique players. Adv Chronic Kidney Dis 18:233-42
Garg, Puneet; Verma, Rakesh; Cook, Leslie et al. (2010) Actin-depolymerizing factor cofilin-1 is necessary in maintaining mature podocyte architecture. J Biol Chem 285:22676-88
Holzman, Lawrence B; Garg, Puneet (2009) Initial insight on the determinants of podocyte polarity. J Am Soc Nephrol 20:683-5