Podocyte expression of the CDK-inhibitor p57 during development and disease

Background. The mature podocyte is a terminally differentiated cell with a limited proliferative capacity. The precise cell cycle proteins necessary f or establishing podocyte quiescence during development or permitting podocy te cell cycle re-entry in disease states have not been fully defined. Accor dingly, we studied the role of the cyclin dependent kinase (CDK)-inhibitor p57(Kip2) (p57) in modulating these processes. Methods. The expression of p57 protein in relation to markers of DNA synthe sis was examined in developing mouse kidneys, and in the passive Heymann ne phritis (PHN) and anti-glomerular antibody models of glomerular disease by immunohistochemistry. The role of p57 in glomerulogenesis was explored by e xamining renal tissue from embryonic p57-/- mice, and the expression of p21 , p27 and p57 protein and mRNA was examined in podocytes in vitro. Results. The de novo expression of p57 during glomerulogenesis coincides wi th the cessation of podocyte proliferation, and the establishment of a matu re phenotype, and p57 is expressed exclusively in podocytes in mature glome ruli. However, p57 knockout mice have normal glomerular podocyte developmen t. In addition, mRNA but not protein levels of p57 increased upon different iation of podocytes in vitro. There was a marked decrease in p57 expression in both animal models of podocyte injury. This was diffuse in PHN, whereas in the murine model, loss of expression of p57 occurred predominantly in p roliferating podocytes, expressing proliferating cell nuclear antigen (PCNA ). Conclusion. Despite the de novo expression of p57 protein coinciding with t he cessation of primitive podocyte proliferation during glomerulogenesis, e mbryonic p57-/- mice glomeruli were histologically normal. Cultured podocyt es did not require changes in p57 protein levels to undergo differentiation . These data suggest that p57 alone is not required for podocyte differenti ation, and that other cell cycle regulators may play a role. Furthermore, a lthough injury to mature podocytes in experimental glomerular disease is as sociated with a decrease in p57, the levels of all three members of the Cip /Kip family of CDK inhibitors appear to determine the capability of podocyt es to proliferate.