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?

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Item Type:	Article
Title:	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?
Creators Name:	Batenburg, W.W., Lu, X., Leijten, F., Maschke, U., Mueller, D.N. and Danser, A.H.J.
Abstract:	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.
Keywords:	Prorenin, DNA Synthesis, Transgenic, (Pro)Renin Receptor, Renin, Plasminogen Activator Inhibitor 1, ERK1/2, Angiotensinogen, Cultured Cells, DNA Replication, Dimerization, Drug Dose-Response Relationship, Extracellular Signal-Regulated MAP Kinases, Vascular Smooth Muscle, Smooth Muscle Myocytes, Phosphorylation, Protein Interaction Mapping, Post-Translational Protein Processing, Cell Surface Receptors, Recombinant Fusion Proteins, Animals, Rats
Source:	Hypertension
ISSN:	0194-911X
Publisher:	American Heart Association
Volume:	58
Number:	6
Page Range:	1111-1119
Date:	December 2011
Official Publication:	https://doi.org/10.1161/HYPERTENSIONAHA.111.180737
PubMed:	View item in PubMed

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