Prorenin and Renin-Induced Extracellular Signal–Regulated Kinase 1/2 Activation in Monocytes Is Not Blocked by Aliskiren or the Handle-Region Peptide

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 51; no. 3; pp. 682 - 688
• Main Authors: Feldt, Sandra, Batenburg, Wendy W, Mazak, Istvan, Maschke, Ulrike, Wellner, Maren, Kvakan, Heda, Dechend, Ralf, Fiebeler, Anette, Burckle, Celine, Contrepas, Aurelie, Danser, A H. Jan, Bader, Michael, Nguyen, Genevieve, Luft, Friedrich C, Muller, Dominik N
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.03.2008; Hagerstown, MD Lippincott
• Subjects: Amides - pharmacology; Angiotensin II - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Endocrine kidney. Renin-angiotensin-aldosterone system; Enzyme Activation - drug effects; Fumarates - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Monocytes - drug effects; Monocytes - enzymology; Oligopeptides - pharmacology; Peptides - pharmacology; Phosphorylation - drug effects; Protein Binding - drug effects; Renin - antagonists & inhibitors; Renin - genetics; Renin - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; U937 Cells; Vertebrates: endocrinology; Hypertension; Monocyte; Enzyme; Enzyme inhibitor; Aliskiren; Non peptide compound; Cardiovascular disease; Peptidases; Signal transduction; Renin; Prorenin; Hydrolases; Antihypertensive agent; Aspartic endopeptidases; (pro)renin receptor
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.107.101444

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 I-renin or I-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.