(Taken directly from the application) The glomerular visceral epithelial cell (VEC) or podocyte is injured in immune and non-immune mediated glomerular disease. In contrast to the marked proliferation that follows injury to the glomerular mesangial and endothelial cells, VEC do not proliferate but rather hypertrophy. These growth responses of VEC are maladaptive and underlie the development of progressive glomerulosclerosis. Cell growth is controlled at the level of the cell cycle by cell cycle regulatory proteins. Proliferation requires that cyclin-dependent kinases (CDK) be activated by specific cyclins. Cyclin kinase inhibitors (CKI) inhibitor proliferation by inhibiting cyclin-CDK complexes, but a role for CKI in mediating cell hypertrophy is not known. This project will test the hypothesis that specific CKIs (p21, p27 and p57) determine the VEC growth response to injury. In the first specific aim, we determine the VEC growth response to injury. In the first specific aim, we propose that VEC can proliferate in vitro and in experimental models of glomerular disease in the levels of CKI are lowered, and that if CKI levels are increased following injury, VEC will not proliferate, but rather hypertrophy. To lower CKI levels in vitro, we will use VEC in culture derived from CKI (p21, p27 and p57) knockout nd wild-type mice. VEC in vitro will be stably transfected to increase CKI levels. A role for CKI in determining the growth response (proliferation, hypertrophy) in vivo will be determined by inducing immune and non-immune forms of VEC injury in CKI (p21, p27 and p57) knockout and wild-type mice. In the second aim, we will test the hypothesis that the Wilms Tumor gene product (WT-1), a transcriptional activator or suppressor and a protein required for normal kidney development, inhibits VEC proliferation and that this is due to the up-regulation of specific CD1. Accordingly, we will measure proliferation in VEC in vitro where the levels of WT-1 are increased (Over-expression) or decreased (antisense), and correlate this with the levels of CKI (p21, p27 and p57). The expression of WT-1 and CKI will be correlated in a variety of animal models of glomerular injury to VEC, and during normal glomerulogenesis. The data generated will provide novel insights into the events that precede and underlie progressive glomerulosclerosis, and should lead to opportunities for potential new therapeutic interventions.
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| Petermann, Arndt T; Pippin, Jeffrey; Durvasula, Raghu et al. (2005) Mechanical stretch induces podocyte hypertrophy in vitro. Kidney Int 67:157-66 |
| Vaughan, Michael R; Pippin, Jeffrey W; Griffin, Sian V et al. (2005) ATRA induces podocyte differentiation and alters nephrin and podocin expression in vitro and in vivo. Kidney Int 68:133-44 |
| Griffin, Sian V; Krofft, Ronald D; Pippin, Jeffrey W et al. (2005) Limitation of podocyte proliferation improves renal function in experimental crescentic glomerulonephritis. Kidney Int 67:977-86 |
| Griffin, Sian V; Hiromura, Keiju; Pippin, Jeffrey et al. (2004) Cyclin-dependent kinase 5 is a regulator of podocyte differentiation, proliferation, and morphology. Am J Pathol 165:1175-85 |
| Cybulsky, Andrey V; Takano, Tomoko; Papillon, Joan et al. (2004) Renal expression and activity of the germinal center kinase SK2. Am J Physiol Renal Physiol 286:F16-25 |
| Durvasula, Raghu V; Petermann, Arndt T; Hiromura, Keiju et al. (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30-9 |
| Hudkins, Kelly L; Gilbertson, Debra G; Carling, Matthew et al. (2004) Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol 15:286-98 |
| Francki, Aleksandar; McClure, Timothy D; Brekken, Rolf A et al. (2004) SPARC regulates TGF-beta1-dependent signaling in primary glomerular mesangial cells. J Cell Biochem 91:915-25 |
| Petermann, Arndt; Hiromura, Keiju; Pippin, Jeffrey et al. (2004) Differential expression of d-type cyclins in podocytes in vitro and in vivo. Am J Pathol 164:1417-24 |
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