Ramipril inhibits in vitro human mesangial cell proliferation and platelet-derived growth factor expression

Angiotensin-converting enzyme (ACE) inhibitors a re antihypertensive drugs that have been shown to reduce proteinuria and to slow down the progression of renal function deterioration in different models of chronic glomerular disease. Major pathogenetic features of progressive glomerular injury leadi ng to glomerulosclerosis are mesangial cell proliferation and platelet-deri ved growth factor (PDGF) expression. The aim of the present study was to ev aluate the effect of ramipril, an ACE inhibitor, on these two potentia I th erapeutic targets. Th us, the effect of ramipril on DNA synthesis, cell pro liferation and PDGF A and B chain gene expression in fetal calf serum (FCS) -activated cultured human glomerular mesangial cells was investigated. DNA synthesis was evaluated by tritiated thymidine incorporation, cell prolifer ation by direct cell counting and cell viability by 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide (MTT). PDGF A and B chain gene expres sions were studied by Northern blot and RT-PCR, respectively. In a dose-dep endent manner ramipril inhibited the FCS-induced DNA synthesis and cell pro liferation. This effect was not dependent upon a toxic effect as demonstrat ed by MTT. The antiproliferative effect of ramipril was most likely indepen dent of its ability to inhibit ACE present in the FCS and/or expressed by t he cells, since a synthetic peptide that specifically inhibits ACE, at the same molar concentrations, did not inhibit FCS-stimulated DNA synthesis. Mo reover, ramipril significantly reduced FCS-induced PDGF A and B chain gene expression. Finally, ramipril completely abolished the PDGF A and B chain g ene expression induced by phorbol 12-myristate 13-acetate, a specific prote in kinase C activator, suggesting a site of action downstream of this enzym e in the mitogenic signal transduction pathway. Our study would suggest tha t the modulatory action of ramipril on activated mesangial cell proliferati on and PDGF expression is independent of its ability to inhibit ACE and cou ld represent an additional mechanism in the renal protective effects of thi s drug.