on January 22, 2008
Published online before print January 22, 2008, doi: 10.1161/HYPERTENSIONAHA.107.101444
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Submitted on September 18, 2007
From the Medical Faculty of the Charité (S.F., H.K., R.D., A.F., F.C.L., D.N.M.), Experimental and Clinical Research Center, Franz Volhard Clinic and HELIOS Klinikum, Berlin-Buch, Germany; Max-Delbrück-Center for Molecular Medicine (I.M., U.M., M.W., C.B., M.B., F.C.L., D.N.M.), Berlin-Buch, Germany; Institut National de la Santé et de la Recherche Médicale (A.C., G.N.), Unit 833, and Collège de France, Chaire de Médecine Expérimentale, Paris, France; and the Department of Pharmacology (W.W.B., A.H.J.D.), Erasmus MC, Rotterdam, The Netherlands. * To whom correspondence should be addressed. E-mail: dominik.mueller{at}mdc-berlin.de.
Abstract—The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal–regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of 125I-renin or 125I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate–labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.
Revised on October 5, 2007
Prorenin and Renin-Induced Extracellular Signal–Regulated Kinase 1/2 Activation in Monocytes Is Not Blocked by Aliskiren or the Handle-Region Peptide
Sandra Feldt;
Key words: renin • prorenin • (pro)renin receptor • aliskiren • signal transduction
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