Published online before print August 28, 2006, doi: 10.1161/01.HYP.0000240064.19301.1b
(Hypertension. 2006;48:564.)
© 2006 American Heart Association, Inc.
Original Articles |
Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II
From the Departments of Pharmacology (J.J.S., I.M.G., A.H.J.D.) and Biochemistry (D.H.W.D., J.M.J.L.), Erasmus MC, Rotterdam, The Netherlands; the Center for Human and Clinical Genetics (P.A.C.t.H., J.T.d.D.), and the Leiden Genome Technology Center (J.T.d.D.), Leiden University Medical Center, Leiden, The Netherlands.
Correspondence to A.H. Jan Danser, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail a.danser{at}erasmusmc.nl
Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (n=4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (P<0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were overrepresented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timp1, Best5, Hsp27, pro-Anp, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensin-independent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression.
Key Words: p38 MAP kinase • actin • microarray • hypertrophy • HSP27
Related Article:
Hypertension 2006 48: 549-551.
This article has been cited by other articles:
 |
|
 |
|
  J. Ino, C. Kojima, M. Osaka, K. Nitta, and M. Yoshida Dynamic Observation of Mechanically-Injured Mouse Femoral Artery Reveals an Antiinflammatory Effect of Renin Inhibitor Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1858 - 1863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Peters, T. Schluter, T. Riegel, B. S. Peters, A. Beineke, U. Maschke, N. Hosten, J. J. Mullins, and R. Rettig Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1845 - H1852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.H. J. Danser (Pro)renin Receptor and Vacuolar H+-ATPase Hypertension, August 1, 2009; 54(2): 219 - 221. [Full Text] [PDF]
|
|
|
|
|
|
C. Mercure, G. Prescott, M.-J. Lacombe, D. W. Silversides, and T. L. Reudelhuber Chronic Increases in Circulating Prorenin Are not Associated With Renal or Cardiac Pathologies Hypertension, June 1, 2009; 53(6): 1062 - 1069. [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]
|
|
|
|
 |
|
 S. Klotz, D. Burkhoff, I. M. Garrelds, F. Boomsma, and A.H.J. Danser The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renin-angiotensin-aldosterone system: therapeutic consequences? Eur. Heart J., April 1, 2009; 30(7): 805 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Singh, B. Le, R. Khode, K. M. Baker, and R. Kumar Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis Diabetes, December 1, 2008; 57(12): 3297 - 3306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, N. A. Noble, W. A. Border, R. T. Owens, and Y. Huang Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E810 - E819. [Abstract] [Full Text] [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]
|
|
|
|
 |
|
 M. J. Brown Aliskiren Circulation, August 12, 2008; 118(7): 773 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. W. Batenburg, R. J.A. de Bruin, J. M.G. van Gool, D. N. Muller, M. Bader, G. Nguyen, and A. H. J. Danser Aliskiren-Binding Increases the Half Life of Renin and Prorenin in Rat Aortic Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, June 1, 2008; 28(6): 1151 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Kang, I. Toma, A. Sipos, E. J. Meer, S. L. Vargas, and J. Peti-Peterdi The Collecting Duct Is the Major Source of Prorenin in Diabetes Hypertension, June 1, 2008; 51(6): 1597 - 1604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Nguyen and A. H. J. Danser Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents Exp Physiol, May 1, 2008; 93(5): 557 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Campbell Critical Review of Prorenin and (Pro)renin Receptor Research Hypertension, May 1, 2008; 51(5): 1259 - 1264. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Feldt, U. Maschke, R. Dechend, F. C. Luft, and D. N. Muller The Putative (Pro)renin Receptor Blocker HRP Fails to Prevent (Pro)renin Signaling J. Am. Soc. Nephrol., April 1, 2008; 19(4): 743 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Feldt, W. W. Batenburg, I. Mazak, U. Maschke, M. Wellner, H. Kvakan, R. Dechend, A. Fiebeler, C. Burckle, A. Contrepas, et al. Prorenin and Renin-Induced Extracellular Signal-Regulated Kinase 1/2 Activation in Monocytes Is Not Blocked by Aliskiren or the Handle-Region Peptide Hypertension, March 1, 2008; 51(3): 682 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Gradman and R. Kad Renin inhibition in hypertension. J. Am. Coll. Cardiol., February 5, 2008; 51(5): 519 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bader Spotlight on Renin: The second life of the (Pro)renin receptor Journal of Renin-Angiotensin-Aldosterone System, December 1, 2007; 8(4): 205 - 208. [PDF]
|
|
|
|
|
|
A. J. Danser Renin Academy in Focus Journal of Renin-Angiotensin-Aldosterone System, December 1, 2007; 8(4): 212 - 212. [PDF]
|
|
|
|
 |
|
 H. Kobori, M. Nangaku, L. G. Navar, and A. Nishiyama The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease Pharmacol. Rev., September 1, 2007; 59(3): 251 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Moore, P. Dicker, J. K. O'Brien, M. Stojanovic, R. M. Conroy, A. Treumann, E. T. O'Brien, D. Fitzgerald, D. Shields, and A. V. Stanton Renin Gene Polymorphisms and Haplotypes, Blood Pressure, and Responses to Renin-Angiotensin System Inhibition Hypertension, August 1, 2007; 50(2): 340 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Jan Danser, W. W. Batenburg, and J. H. M. van Esch Prorenin and the (pro)renin receptor--an update Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1288 - 1292. [Full Text] [PDF]
|
|
|
|
|
|
J. L Zhuo and X. C Li Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells Journal of Renin-Angiotensin-Aldosterone System, March 1, 2007; 8(1): 23 - 33. [Abstract] [PDF]
|
|
|
|
 |
|
 W. C. De Mello On the Pathophysiological Implications of an Intracellular Renin Receptor Circ. Res., December 8, 2006; 99(12): 1285 - 1286. [Full Text] [PDF]
|
|
|
|
|
|
C. Burckle and M. Bader Prorenin and Its Ancient Receptor Hypertension, October 1, 2006; 48(4): 549 - 551. [Full Text] [PDF]
|
|