Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin
Genevieve Nguyen, … , Thomas Giller, Jean-Daniel Sraer
Genevieve Nguyen, … , Thomas Giller, Jean-Daniel Sraer
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1417-1427. https://doi.org/10.1172/JCI14276.
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Article Vascular biology

Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

Abstract

Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors. We report the expression cloning of the human renin receptor complementary DNA encoding a 350–amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2. High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver. By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin. The renin receptor is the first described for an aspartyl protease. This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.

Authors

Genevieve Nguyen, Françoise Delarue, Céline Burcklé, Latifa Bouzhir, Thomas Giller, Jean-Daniel Sraer

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Intracellular calcium and cAMP changes, MAP kinases ERK1(p44)/ERK2(p42) ...
Intracellular calcium and cAMP changes, MAP kinases ERK1(p44)/ERK2(p42) activation induced by renin. (a) Cells expressing the receptor were stimulated by 100 nM renin, and the intracellular calcium changes were analyzed by spectrofluorometry (top). Cell stimulation by human thrombin (10 nM) was used as control. Analysis of intracellular cAMP changes by cells stimulated by 10 nM renin and by 1 μM PGE-1 or by 1 μM isoproterenol (Isop), as positive controls (bottom). The results represent the mean ± SD of two experiments performed in triplicate. *P < 0.05 compared with basal value. (b) HMC2 cells (left panel) or control cells (right panel) were stimulated with renin in the presence of 1 μM Losartan. At intervals, the cells were lysed and the lysate analyzed by Western blotting using Ab’s to active or to total ERK1 and ERK2. The blots were scanned and the ratio of active, phosphorylated ERK1/ERK2 to total ERK1/ERK2 was plotted using the NIH IMAGE program. MAP kinase activity assay was performed on HMC2 renin-stimulated cells (left bottom). The results are expressed as 32P incorporated and represent the mean ± SD of two experiments performed in triplicate. *P < 0.05 compared with basal value.