Glomerular diseases remain a leading cause of kidney failure in the US. Injury to podocytes (visceral glomerular epithelial cell) in diabetic and membranous nephropathy, focal segmental glomerular sclerosis and minimal change disease, results in proteinuria, but if not adequately repaired, leads progressive glomerular sclerosis and reduced renal function. In order to perform a highly specialized function, podo are terminally differentiated in quiescent cells. Studies have shown that the apparent inability to proliferate and replace those podocytes lost by detachment/apoptosis, is central to the development of progressive glomerulosclerosis. Studies have shown that intraglomerular capillary pressure (Pgc) increases in most forms of progressive glomerular disease such as diabetic nephropathy. Increased Pgc, and the resultant mechanical stretch, is therefore considered a final common pathway to glomerulosclerosis. Although increased Pgc is associated with podo injury, the mechanisms are not known. In the first Specific Aim, we will apply mechanical stretch mouse podocytes in vitro to induce stress-tension injury. We will test the central hypothesis that stress-tension inhibits podo proliferation and induces hypertrophy. We will test the hypothesis that stretch increases the levels of CDK-inhibitors (p21, p27, p57), thereby inhibiting proliferation, and inducing hypertrophy. Specific null podo be used for study. We will also test the hypothesis that 3beta1 integrin and integrin-linked kinase mediate these growth effects (anti-proliferation, hypertrophy) and we will examine how specific signaling pathways (ERK1/2, Akt) mediate these events. In the second specific aim we will test the hypothesis that cyclin I and cyclin-dependent kinase (CDK) 5, recently identified cell cycle proteins, regulate podo proliferation and differentiation. Although podo do not typically proliferate following injury, podo de-differentiate and re-enter the cell cycle in HIV nephropathy. Our exciting preliminary data shows that cyclin and CDK5 are constitutively expressed in podo. Utilizing mouse podocytes in culture, and CDK5 and cyclin I null mice, we will examine podo differentiation, proliferation and phenotype during development and in disease. Finally, we will also test the novel hypothesis that cyclin I regulates CDK5, and that CDK5 is the catalytic partner for cyclin I. Taken together, the overall goal is to show novel mechanisms underlying podo injury, so that ultimately, specific therapeutic strategies can be developed to reduce podo injury in the development of glomerular sclerosis.
| Jefferson, J Ashley; Shankland, Stuart J (2014) The pathogenesis of focal segmental glomerulosclerosis. Adv Chronic Kidney Dis 21:408-16 |
| Taniguchi, Yoshinori; Pippin, Jeffrey W; Hagmann, Henning et al. (2012) Both cyclin I and p35 are required for maximal survival benefit of cyclin-dependent kinase 5 in kidney podocytes. Am J Physiol Renal Physiol 302:F1161-71 |
| Jefferson, J Ashley; Alpers, Charles E; Shankland, Stuart J (2011) Podocyte biology for the bedside. Am J Kidney Dis 58:835-45 |
| Marshall, Caroline B; Krofft, Ron D; Blonski, Mary J et al. (2011) Role of smooth muscle protein SM22? in glomerular epithelial cell injury. Am J Physiol Renal Physiol 300:F1026-42 |
| Brinkkoetter, Paul T; Pippin, Jeffrey W; Shankland, Stuart J (2010) Cyclin I-Cdk5 governs survival in post-mitotic cells. Cell Cycle 9:1729-31 |
| Brinkkoetter, Paul T; Wu, Jimmy S; Ohse, Takamoto et al. (2010) p35, the non-cyclin activator of Cdk5, protects podocytes against apoptosis in vitro and in vivo. Kidney Int 77:690-9 |
| Hauser, Peter V; Pippin, Jeffrey W; Kaiser, Cora et al. (2010) Novel siRNA delivery system to target podocytes in vivo. PLoS One 5:e9463 |
| Marshall, Caroline B; Krofft, Ron D; Pippin, Jeffrey W et al. (2010) CDK inhibitor p21 is prosurvival in adriamycin-induced podocyte injury, in vitro and in vivo. Am J Physiol Renal Physiol 298:F1140-51 |
| Ohse, Takamoto; Pippin, Jeffrey W; Chang, Alice M et al. (2009) The enigmatic parietal epithelial cell is finally getting noticed: a review. Kidney Int 76:1225-38 |
| Hauser, Peter V; Perco, Paul; Mühlberger, Irmgard et al. (2009) Microarray and bioinformatics analysis of gene expression in experimental membranous nephropathy. Nephron Exp Nephrol 112:e43-58 |
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