Role of cyclins in cAMP inhibition of glomerular mesangial cell proliferation.

MC (mesangial cell) proliferation is closely linked to the progression of glomerular disease. It has been reported that cAMP effectors suppress MC proliferation, inhibiting activation of MAPK (mitogen-activated protein kinase). In fibroblasts, activation of MAPK induces the expression of type D cyclin, whereas, in MCs, this induction has not been shown. In the present study, we explored the effects of cAMP on MAPK and expression of cell-cycle-regulated proteins. PDGF (platelet-derived growth factor) stimulated MAPK activity, up-regulated protein levels of cyclin D1, CDK2 (cyclin-dependent kinase 2) and PCNA (proliferating cell nuclear antigen), decreased the protein level of p27 and increased DNA synthesis. Fsk (forskolin) or PD98059 suppressed PDGF-induced DNA synthesis. Both agents inhibited PDGF-stimulated mRNA and protein expression of cyclin D1 and CDK2. Fsk or PD98059 also inhibited protein expression of PCNA and blocked a decrease in p27 protein. Fsk induced the phosphorylation of Raf-1 at Ser259, which was inhibited by KT5720. These data suggest that cAMP inhibits MC proliferation through inhibition of MAPK activity, and this mechanism partly involves alteration in the levels of cell-cycle-regulated proteins.