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?

被引：57

作者：

Batenburg, Wendy W. ^{[1
]}

Lu, Xifeng ^{[1
]}

Leijten, Frank ^{[1
]}

Maschke, Ulrike ^{[2
]}

Mueller, Dominik N. ^{[2
,3
]}

Danser, A. H. Jan ^{[1
]}

机构：

[1] Erasmus MC, Div Pharmacol & Vasc Med, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands

[2] Max Delbruck Ctr Mol Med, Berlin, Germany

[3] Univ Erlangen Nurnberg, Dept Expt Med, Erlangen, Germany

来源：

HYPERTENSION | 2011年 / 58卷 / 06期

关键词：

prorenin; DNA synthesis; transgenic; (pro)renin receptor; renin; plasminogen activator inhibitor 1; ERK1/2; VACUOLAR H+-ATPASE; ANGIOTENSIN-II; TRANSGENIC RATS; NONPROTEOLYTIC ACTIVATION; PROTEIN-KINASE; BLOOD-PRESSURE; HANDLE-REGION; GROWTH-FACTOR; EXPRESSION; INCREASES;

D O I：

10.1161/HYPERTENSIONAHA.111.180737

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

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 (approximate to 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, approximate to 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 (approximate to 4000-fold above normal) it activated extracellular signal-regulated kinase 1/2 directly (ie, independent of angiotensin). Renin at concentrations of 1 nmol/L (approximate to 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. (Hypertension. 2011;58:1111-1119.)

引用

页码：1111 / 1119

页数：9

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