Renin- and Prorenin-Induced Effects in Rat Vascular Smooth Muscle Cells Overexpressing the Human (Pro)Renin Receptor: Does (Pro)Renin-(Pro)Renin Receptor Interaction Actually Occur?

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 58; no. 6; pp. 1111 - 1119
• Main Authors: Batenburg, Wendy W, Lu, Xifeng, Leijten, Frank, Maschke, Ulrike, Müller, Dominik N, Danser, A.H Jan
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.12.2011; Lippincott Williams & Wilkins
• Subjects: Angiotensinogen - biosynthesis; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Dimerization; DNA Replication - drug effects; Dose-Response Relationship, Drug; Endocrine kidney. Renin-angiotensin-aldosterone system; Extracellular Signal-Regulated MAP Kinases - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; Phosphorylation - drug effects; Plasminogen Activator Inhibitor 1 - secretion; Protein Interaction Mapping; Protein Processing, Post-Translational - drug effects; Rats; Rats, Transgenic; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - physiology; Recombinant Fusion Proteins - physiology; Renin - pharmacology; Vertebrates: endocrinology; Human; Hypertension; Rat; Enzyme; Rodentia; Smooth muscle; Cardiovascular disease; DNA synthesis; Peptidases; Plasminogen activator inhibitor 1; Vertebrata; ERK1/2; Mammalia; Renin; Animal; Prorenin; Hydrolases; Aspartic endopeptidases; transgenic; (pro)renin receptor
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.111.180737

Renin/prorenin binding to the (pro)renin receptor ([P]RR) results in direct (angiotensin-independent) second-messenger activation in vitro, whereas in vivo studies in rodents overexpressing prorenin (≈400-fold) or the (P)RR do not support such activation. To solve this discrepancy, DNA synthesis, extracellular signal–regulated kinase 1/2 phosphorylation, and plasminogen-activator inhibitor 1 release were evaluated in wild-type and human (P)RR-overexpressing vascular smooth muscle cells after their incubation with 1 to 80 nmol/L of (pro)renin. Human prorenin (4 nmol/L, ie, ≈800-fold above normal) + angiotensinogen increased DNA synthesis in human (P)RR cells only in an angiotensin II type 1 receptor–dependent manner. Prorenin at this concentration also increased plasminogen-activator inhibitor 1 release via angiotensin. Prorenin alone at 4 nmol/L was without effect, but at 20 nmol/L (≈4000-fold above normal) it activated extracellular signal–regulated kinase 1/2 directly (ie, independent of angiotensin). Renin at concentrations of 1 nmol/L (≈2000-fold above normal) and higher directly stimulated DNA synthesis, extracellular signal–regulated kinase 1/2 phosphorylation, and plasminogen-activator inhibitor 1 release in wild-type and human (P)RR cells, and similar effects were seen for rat renin, indicating that they were mediated via the rat (P)RR. In conclusion, angiotensin generation depending on prorenin-(P)RR interaction may occur in transgenic rodents overexpressing prorenin several 100-fold. Direct (pro)renin-induced effects via the (P)RR require agonist concentrations that are far above the levels in wild-type and transgenic rats. Therefore, only prorenin (and not [P]RR) overexpression will result in an angiotensin-dependent phenotype, and direct renin-(P)RR interaction is unlikely to ever occur in nonrenin-synthesizing organs.