Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells
Renin inhibition with aliskiren has been reported to cause a greater rise in renin than other types of renin-angiotensin system blockade, thereby potentially leading to angiotensin generation or stimulation of the human (pro)renin receptor (h(P)RR). Here we studied whether this rise in renin is attributable to an aliskiren-induced change in the prorenin conformation, allowing its detection in renin assays, or a change in renin/prorenin clearance. We also investigated whether aliskiren affects (pro)renin binding to its receptors, using rat aortic vascular smooth muscle cells (VSMCs) overexpressing the h(P)RR. Methods and Results-A 48-hour incubation with aliskiren at 40C converted the prorenin conformation from "closed" to "open," thus allowing its recognition in active site-directed renin assays. VSMCs accumulated (pro)renin through binding to mannose 6-phosphate receptors (M6PRs) and h(P)RRs. Aliskiren did not affect binding at 40C. At 370C, aliskiren increased (pro)renin accumulation up to 40-fold, and M6PR blockade prevented this. Aliskiren increased the intracellular half life of prorenin 2 to 3 times. Conclusion-Aliskiren allows the detection of prorenin as renin, and decreases renin/prorenin clearance. Both phenomena may contribute to the "renin" surge during aliskiren treatment, but because they depend on aliskiren binding, they will not result in angiotensin generation. Aliskiren does not affect (pro)renin binding to its receptors.
|Keywords||Aliskiren, Half-life, Prorenin, Receptor, Renin|
|Persistent URL||dx.doi.org/10.1161/ATVBAHA.108.164210, hdl.handle.net/1765/30141|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|Note||Free full text at PubMed|
Batenburg, W.W, de Bruin, R.J.A, van Gool, J.M, Müller, D, Bader, M, Nguyen, G, & Danser, A.H.J. (2008). Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(6), 1151–1157. doi:10.1161/ATVBAHA.108.164210