Glomerular disease is one of the major causes of end stage renal disease. The mesangial cell injury that accompanies glomerular injury is characterized by cell proliferation, which is linked to matrix accumulation and the development of glomerulosclerosis. Although many of the cytokines that mediate mesangial cell proliferation are known, the nuclear events remain poorly characterized. Cell proliferation is under the control of specific cell cycle regulatory proteins, but the expression of these proteins in inflammation and in the kidney are not known. In the proposed studies the applicant will determine the expression and activity of specific cell cycle proteins in mesangial cell proliferation in vitro and in vivo, and will test the basic hypothesis that two specific cyclin kinase inhibitors, p21 and p27, are major determinants of mesangial proliferation in vitro and in vivo.
The specific aims are: (i) determine the expression of cell cycle proteins in rat and mouse mesangial cell proliferation when stimulated with mitogens, or inhibited by anti-proliferative cytokines; (ii) determine the functional role of p21 and p27 in mesangial cells by studying mesangial cells in culture derived from p21 and p27 knockout mice and ask if these specific cyclin kinase inhibitors are major determinants of the mesangial cell's proliferative response to cytokines; (iii) block cytokines that are upregulated in a disease (Thy1) model of glomerular injury and determine the role of these cytokines on the expression of specific cell cycle proteins in vivo; (iv) determine if p21 and p27 are major determinants of mesangial proliferation and injury in vivo by comparing experimental glomerulonephritis in p21 and p27 knockout mice with p21 and p27 wild-type mice with glomerulonephritis. Insights into the mechanisms of mesangial cell proliferation may provide future therapeutic strategies for glomerular disease.
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