on April 3, 2008
Published online before print April 3, 2008, doi: 10.1161/ATVBAHA.108.164210
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 16, 2007
Accepted on March 21, 2008
Aliskiren-Binding Increases the Half Life of Renin and Prorenin in Rat Aortic Vascular Smooth Muscle Cells
Wendy W. Batenburg ;
From the Erasmus MC (W.W.B., R.J.A.d.B., J.M.G.v.G., A.H.J.D.), Rotterdam, The Netherlands; Max Delbrück Center for Molecular Medicine (D.N.M., M.B.), Berlin, Germany; and the Institut National de Santé et de la Recherche Médicale (Inserm) Unit 833 and Chaire de Médecine Expérimentale (G.N.), Collège de France, Paris, France.
* To whom correspondence should be addressed. E-mail: a.danser{at}erasmusmc.nl.
Objective—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 VSMCs overexpressing the h(P)RR.
Methods and Results—A 48-hour incubation with aliskiren at 4°C 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 4°C. At 37°C, 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.
Key words: prorenin • renin • aliskiren • half-life • receptor
This article has been cited by other articles:
 |
|
 |
|
  F. Persson, P. Rossing, H. Reinhard, T. Juhl, C. D.A. Stehouwer, C. Schalkwijk, A.H. J. Danser, F. Boomsma, E. Frandsen, and H.-H. Parving Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria Diabetes Care, October 1, 2009; 32(10): 1873 - 1879. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cousin, D. Bracquart, A. Contrepas, P. Corvol, L. Muller, and G. Nguyen Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma Hypertension, June 1, 2009; 53(6): 1077 - 1082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-H. Parving, B. M. Brenner, John. J. V. McMurray, D. de Zeeuw, S. M. Haffner, S. D. Solomon, N. Chaturvedi, M. Ghadanfar, N. Weissbach, Z. Xiang, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1663 - 1671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Krop, I. M. Garrelds, R. J.A. de Bruin, J. M.G. van Gool, N. D.L. Fisher, N. K. Hollenberg, and A.H. Jan Danser Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin Hypertension, December 1, 2008; 52(6): 1076 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dietz, R. Dechend, C.-M. Yu, M. Bheda, J. Ford, M. F. Prescott, and D. L. Keefe Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension1 Journal of Renin-Angiotensin-Aldosterone System, September 1, 2008; 9(3): 163 - 175. [Abstract] [PDF]
|
|
|
|
|
|
W. W Batenburg and A. J. Danser Prorenin and the (pro)renin receptor: binding kinetics, signalling and interaction with aliskiren Journal of Renin-Angiotensin-Aldosterone System, September 1, 2008; 9(3): 181 - 184. [PDF]
|
|
|
|
|
|
A. J. Danser and G. Nguyen Spotlight on Renin: The Renin Academy Summit: advancing the understanding of renin science Journal of Renin-Angiotensin-Aldosterone System, June 1, 2008; 9(2): 119 - 123. [PDF]
|
|