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.

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells

“…This protein can bind prorenin with a nanomolar-range dissociation constant (K D ), similar to what was reported for full-length (P)RR expressed on the cell membrane 1,3,4 or in a baculovirus expression system. 13 Prorenin showed renin activity when incubated with cultured HUVEC medium at 25 1C.…”

“…1,2 Catalytic activity of renin increases several fold after binding to this receptor. 1,3 Also, prorenin, a physiologically inactive precursor molecule, shows renin activity after binding to (P)RR.…”

“…1,2 Catalytic activity of renin increases several fold after binding to this receptor. 1,3 Also, prorenin, a physiologically inactive precursor molecule, shows renin activity after binding to (P)RR. 1,[3][4][5] Functional (P)RR on the membrane is able to induce signal transduction cascades after ligand binding via receptor phosphorylation and activation of the mitogen-activated protein kinases ERK1/2.…”

“…1,3 Also, prorenin, a physiologically inactive precursor molecule, shows renin activity after binding to (P)RR. 1,[3][4][5] Functional (P)RR on the membrane is able to induce signal transduction cascades after ligand binding via receptor phosphorylation and activation of the mitogen-activated protein kinases ERK1/2. 1,6 This receptor is involved in pathological events, such as diabetic retinopathy, nephropathy and hypertension.…”

“…1,[3][4][5] Functional (P)RR on the membrane is able to induce signal transduction cascades after ligand binding via receptor phosphorylation and activation of the mitogen-activated protein kinases ERK1/2. 1,6 This receptor is involved in pathological events, such as diabetic retinopathy, nephropathy and hypertension. [7][8][9] Overexpressed (P)RR in smooth muscle cells causes elevated blood pressure and increased heart rate, 10 and glomerulosclerosis and proteinuria have been reported in transgenic models in which (P)RR is overexpressed.…”