The role of cyclin dependent kinase-5 in podocytes differentiation and maintenance of podocytes shape and its function.

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We investigated the role of cyclin dependent kinase 5 (CDK5) in podocytes differentiation and the maintenance of podocytes shape and its function, using mice model of HIV nephropathy. The mice (rtTA-Vpr) were generated to express one of HIV accessory protein, Vpr, predominantly in podocytes, using podocin promoter and tet-on system. By the combination of heminephrectomy and administration of doxycycline, mice developed collapsing or cellular type focal segmental sclerosis with massive proteinuria, resembling human HIV-associated nephropathy. During the development of glomerulosclerosis, dedifferentiation of podocytes was observed. Using this model, we examined the expression of CDK5. The expression of CDK5 decreased and disappeared during the dedifferentiation of podocytes. The markers of podocytes differentiation, such as WT-1 and synaptopodin, similarly decreased and disappeared. We also examined cyclin D3, which binds to CDK5, but not activates CDK5. The expression of cyclin D3 also decreased and disappeared. On the contrary, PCNA, the marker of cell proliferation was detected in dedifferentiated podocytes, demonstrating that these cells were in cell cycle for proliferation. These changes were observed in the podocytes those did not changed morphologically by a light microscope, although at the time when massive proteinuria was already detected.In conclusion, CDK5 and its related protein were shown to decrease and disappear during the podocytes dedifferentiation in mice model of HIV nephropathy, in which massive proteinuria and glomeruloselerosis were observed. These results suggest that CDK5 and its related protein play a role in differentiated podocytes to maintain its function. Loss of these molecules may lead to proteinuria and glomerulosclerosis.