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 into 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 angiotensinogen (ANG) (1.5 x 10(-7) M) and prorenin (10(-8)-10(-7) M) resulted in an efficient production (within 4 h) of angiotensin I, almost completely inhibited by 10(-5) M aliskiren (-86.0 +/- 14.0%). In HSMCs stimulated with both ANG and prorenin, a 24 h incubation with aliskiren (10(-6)-10(-5) M) resulted in a concentration-dependent reduction of PRR mRNA levels (IC50 4.6 x 10(-6) M). The cell surface expression of PRR determined by flow cytometry analysis was also reduced after incubation with aliskiren in a concentration-dependent manner. The lower levels of PRR were associated with a reduced expression of TGF-beta, PAI-1 and type I collagen mRNA. Conclusions: These results suggest a direct pharmacological action of aliskiren on PRR expression and its signalling pathway in HSMCs. This reported action of aliskiren may reveal a new scenario of the pharmacological properties of aliskiren.