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 × 10(-7)M) and prorenin (10(-8)-10(-7)M) resulted in an efficient production (within 4h) of angiotensin I, almost completely inhibited by 10(-5)M aliskiren (-86.0 ± 14.0%). In HSMCs stimulated with both ANG and prorenin, a 24h incubation with aliskiren (10(-6)-10(-5)M) resulted in a concentration-dependent reduction of PRR mRNA levels (IC(50) 4.6 × 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-β, 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.
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 × 10(-7)M) and prorenin (10(-8)-10(-7)M) resulted in an efficient production (within 4h) of angiotensin I, almost completely inhibited by 10(-5)M aliskiren (-86.0 ± 14.0%). In HSMCs stimulated with both ANG and prorenin, a 24h incubation with aliskiren (10(-6)-10(-5)M) resulted in a concentration-dependent reduction of PRR mRNA levels (IC(50) 4.6 × 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-β, 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.
Authors: Mariadelina Simeoni; Ramona Nicotera; Maria Colao; Maria Lucia Citraro; Elena Pelagi; Annamaria Cerantonio; Nicola Comi; Giuseppe Coppolino; Giorgio Fuiano Journal: Int Urol Nephrol Date: 2015-10-05 Impact factor: 2.370
Authors: Wendy W Batenburg; Amrisha Verma; Yunyang Wang; Ping Zhu; Mieke van den Heuvel; Richard van Veghel; A H Jan Danser; Qiuhong Li Journal: PLoS One Date: 2014-06-26 Impact factor: 3.240