ALISKIREN REDUCES PRORENIN RECEPTOR EXPRESSION AND ACTIVITY IN CULTURED HUMAN AORTIC SMOOTH MUSCLE CELLS

Introduction: The recent discovery of a specific receptor for renin/prorenin (PRR) has added new interest to the potential pharmacological actions of aliskiren, the first direct renin inhibitor. Materials and methods: In the present study, to gain new insights on the pharmacological properties of aliskiren, we investigated the effect of aliskiren on PRR expression and activity in cultured human smooth muscle cells (HSMCs). Results: Co-incubation of HSMCs with ANG (1.5•10-7M) and prorenin (10-8÷10-7M) determined an efficient production (within 4h) of angiotensin I, almost completely inhibited by 10-5M aliskiren (-86.0±14.0%). In HSMCs stimulated with both ANG and prorenin, a 24h incubation with aliskiren (10-6÷10-5M) determined a concentration-dependent reduction of PRR mRNA levels (IC50 4.6•10-6M). The cell surface expression of PRR determined by flow cytometry analysis was also reduced after incubation with aliskiren in a concentrations dependent manner. The lower levels of PRR were also associated with a reduced expression of TGF-, PAI-1 and type I collagen mRNA. Conclusions: These results suggest a direct pharmacological action of aliskiren on PRR expression and its signaling pathway in human HSMCs. This reported action of aliskiren may open to a new scenario on the pharmacological properties of aliskiren