on August 28, 2006
Published online before print August 28, 2006, doi: 10.1161/01.HYP.0000240064.19301.1b
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Submitted on May 17, 2006
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. * To whom correspondence should be addressed. E-mail: a.danser{at}erasmusmc.nl.
Abstract--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.
Revised on June 5, 2006
Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II
Jasper J. Saris;
Key words: p38 MAP kinase • actin • microarray • hypertrophy • HSP27
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Hypertension 2006 48: 549-551.
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