Response to Cardiovascular Effects of Nonproteolytic Activation of Prorenin
A great deal of attention has been focused on the receptor-associated prorenin system triggered by binding of prorenin to the prorenin receptor.1 Recent studies have demonstrated that the receptor-associated prorenin system contributes to the pathogenesis of end-organ damage in hypertension2 and diabetes mellitus3 and consists of 2 major pathways: conversion of prorenin to an active form by a conformational change, that is, nonproteolytic activation of prorenin followed by activation of the tissue renin–angiotensin system3 and stimulation of tyrosine phosphorylation as a result of activation of the prorenin receptor by its ligand (prorenin), leading to activation of the extracellular signal–related protein kinases.4 Prorenin receptor blockade is, therefore, thought to be of greater benefit than conventional renin–angiotensin system inhibitors in preventing the end-organ damage in hypertension and diabetes mellitus.
We appreciate the letter by Susic et al5 and agree with their findings that 4-week treatment of spontaneously hypertensive rats with the “handle region” decoy peptide, which competitively binds to the prorenin receptor, significantly reduces left ventricular mass without affecting myocardial collagen content, left ventricular function, or coronary and renal hemodynamics, although 8-week treatment of stroke-prone spontaneously hypertensive rats with the decoy peptide significantly attenuated cardiac fibrosis.2 As they stated, the effectiveness of prorenin receptor blockade may depend on the dose of inhibitor and the duration of exposure to it, and the nonproteolytic activation of prorenin may make a major contribution to the end-organ damage in acute and severe forms of hypertension. However, the decoy peptide is a competitive antagonist of prorenin for binding to the receptor, and because we recently found that the decoy peptide elicits weak activation of extracellular signal–related protein kinases in human vascular smooth muscle cells in the absence of prorenin (unpublished data), the decoy peptide is probably a weak prorenin receptor agonist. We hope that a potent, nonpeptide, noncompetitive antagonist will become available for clinical use in the near future.
Danser AH. Prorenin: back into the arena. Hypertension. 2006; 47: 824–826.
Ichihara A, Kaneshiro Y, Takemitsu T, Sakoda M, Suzuki F, Nakagawa T, Nishiyama A, Inagami T, Hayashi M. Non–proteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension. 2006; 47: 894–900.
Ichihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nakagawa T, Tada Y, Koura Y, Nishiyama A, Okada H, Uddin MN, Nabi AHMN, Ishida Y, Inagami T, Saruta T. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for non–proteolytic activation of prorenin. J Clin Invest. 2004; 114: 1128–1135.
Susic D, Lippton H, Knight M, Frohlich ED. Cardiovascular effects of nonproteolytic activation of prorenin. Hypertension. 2006; 48: e113.