H(P)RRs preferentially bind prorenin, and such binding results in angiotensin generation, most likely because binding results in prorenin activation.
Abstract-The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling. Key Words: renin Ⅲ prorenin Ⅲ (pro)renin receptor Ⅲ aliskiren Ⅲ signal transduction A liskiren is a recent Food and Drug Administrationapproved, low-molecular weight, direct renin inhibitor that binds to the enzymatically active cleft of renin. Direct renin inhibition in a double-transgenic rat model of high human renin hypertension demonstrated target organ protection. 1,2 A novel (pro)renin receptor [(P)RR] has been cloned that signals when exposed to either renin or prorenin. 3 The (P)RR, correctly termed "RR/ATP6AP2," is a single transmembrane domain protein of 350 amino acids with a large unglycosylated and highly hydrophobic N-terminal domain and a short cytoplasmic tail of Ϸ20 amino acids. The (P)RR is a protein conserved among species. 4 The (P)RR enhances renin catalytic activity and allows prorenin to display catalytic activity without its proteolytic conversion to renin ("nonproteolytic activation"). Such nonproteolytic activation involves unfolding of the prosegment from the enzymatic cleft, mediated by a (P)RR-induced conformational change in the prorenin molecule. This (P)RR-induced prorenin activation could explain how prorenin exerts pathological effects in diabetic patients, where prorenin represents Յ95% of total circulating renin. Nevertheless, this hypothesis remain...
Background-Angiotensin (Ang) II type 2 (AT 2 ) receptor stimulation results in coronary vasodilation in the rat heart. In contrast, AT 2 receptor-mediated vasodilation could not be observed in large human coronary arteries. We studied Ang II-induced vasodilation of human coronary microarteries (HCMAs). Methods and Results-HCMAs (diameter, 160 to 500 m) were obtained from 49 heart valve donors (age, 3 to 65 years).Ang II constricted HCMAs, mounted in Mulvany myographs, in a concentration-dependent manner (pEC 50 , 8.6Ϯ0.2; maximal effect [E max ], 79Ϯ13% of the contraction to 100 mmol/L K ϩ ). The Ang II type 1 receptor antagonist irbesartan prevented this vasoconstriction, whereas the AT 2 receptor antagonist PD123319 increased E max to 97Ϯ14% (PϽ0.05). The increase in E max was larger in older donors (correlation ⌬E max versus age, rϭ0.47, PϽ0.05). The PD123319-induced potentiation was not observed in the presence of the NO synthase inhibitor L-NAME, the bradykinin type 2 (B 2 ) receptor antagonist Hoe140, or after removal of the endothelium. Ang II relaxed U46619-preconstricted HCMAs in the presence of irbesartan by maximally 49Ϯ16%, and PD123319 prevented this relaxation. Finally, radioligand binding studies and reverse transcription-polymerase chain reaction confirmed the expression of AT 2 receptors in HCMAs. Conclusions-AT 2 receptor-mediated vasodilation in the human heart appears to be limited to coronary microarteries and is mediated by B 2 receptors and NO. Most likely, AT 2 receptors are located on endothelial cells, and their contribution increases with age.
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