Dipyridamole Inhibits PDGF-Stimulated Human Peritoneal Mesothelial Cell Proliferation: Effects on Cyclin Kinase Inhibitors (CKI)

Background. Cytokines-stimulated proliferation of human peritoneal mesothelial cells (HPMC) may contribute to the development of encapsulating peritoneal sclerosis (EPS), which is a serious complication in long-term peritoneal dialysis (PD) patients. We previously (Kidney Int 2001, Sep) had reported that dipyridamole (DP) inhibited HPMC proliferation by platelet-derived growth factor (PDGF). This inhibitory mechanism of DP may result from cell-cycle arrest of HPMC by DP. Cyclin-kinase inhibitors (CKI) negatively regulate the progression of cell-cycle. Two major classes of CLIs have been identified in mammalian cells: the INK4s(p16INK4a, p15INK4b,and p19INK4d)and those able to inhibit all the CDKs (p21Cipl, and p27Kipl). While the p27Kipl have been investigated in HPMc, there is no report detailing the expression of the other CKIs in PDGF-and/or DP-treated HPMC. In this project, we will investigate whether the inhibitory effect of DP on PDGF-stimulated HPMC proliferation operated through modulations of these CKIS. Methods. HPMC was cultured from human omentum. The expression of CKIs in various conditions of HPMC were determined by Western blotting. Results. PDGF (20 μg/ml) stimulated proliferation of HPMC, which were significantly inhibited by DP in a dose-dependent and time-dependent manner. In PDGF-stimulated HPMC, the expressions of p16INK4a and o19 INK4b remained constant until 8th after PDGF then decreased. The protein level of p15INK4b remained low in the presence or absence of PDGF; in contrast, there is persistently high protein level of p21Cip1 before and after treatment with PDGF. DP, at the dosage that inhibited PDGF-stimulated HPMC proliferation, did not alter the expressions of these CKIs (p16INK4a,p15INK4b,p19INK4b and p21Cipl). Conclusion. It seems that DP inhibited PDGF-stimulated HPMC proliferation through meachanisms other than modulations of these CKIs (p16INK4a,p15INK4b,p19INK4b and p21Cipl) in HPMC.