The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling.

The prorenin/renin receptor is a recently discovered component of the renin-angiotensin system. The effects of aliskiren, a direct inhibitor of human renin, were compared with the handle region decoy peptide (HRP), which blocks the prorenin/renin receptor, in double-transgenic rats overexpressing the human renin and angiotensinogen genes. After 7 wk, all aliskiren-treated rats were alive, whereas mortality was 40% in vehicle-treated and 58% in HRP-treated rats. Aliskiren but not the HRP reduced BP and normalized albuminuria, cystatin C, and neutrophil gelatinase-associated lipocalin, a marker of renal tubular damage, to the levels of nontransgenic controls. In vitro, human renin and prorenin induced extracellular signal-regulated kinase 1/2 phosphorylation, independent of angiotensin II (AngII), in vascular smooth muscle cells. Preincubation with the HRP or aliskiren did not prevent renin- and prorenin-induced extracellular signal-regulated kinase 1/2 phosphorylation, whereas the MAP kinase kinase (MEK1/2) inhibitor PD98059 prevented both. In conclusion, renin inhibition but not treatment with the HRP protects against AngII-induced renal damage in double-transgenic rats. In addition, the in vitro data do not support the use of the HRP to block AngII-independent prorenin- or renin-mediated effects.

[1]  S. Oparil,et al.  Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial , 2007, The Lancet.

[2]  F. Luft.  Renin and its putative receptor remain enigmas. , 2007, Journal of the American Society of Nephrology : JASN.

[3]  A. Satlin,et al.  Antihypertensive efficacy, safety, and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. , 2007, Journal of the American Society of Hypertension : JASH.

[4]  W. Border,et al.  Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. , 2007, Kidney international.

[5]  A. Nishiyama,et al.  Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. , 2007, Journal of the American Society of Nephrology : JASN.

[6]  R. Dechend,et al.  Low-dose renin inhibitor and low-dose AT1-receptor blocker therapy ameliorate target-organ damage in rats harbouring human renin and angiotensinogen genes , 2007, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[7]  A. Stanton,et al.  Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker , 2007, Hypertension.

[8]  D. Calhoun,et al.  Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide , 2007, Journal of hypertension.

[9]  P. Pandolfi,et al.  A Novel Signal Transduction Cascade Involving Direct Physical Interaction of the Renin/Prorenin Receptor With the Transcription Factor Promyelocytic Zinc Finger Protein , 2006, Circulation research.

[10]  E. Frohlich,et al.  Cardiovascular effects of nonproteolytic activation of prorenin. , 2006, Hypertension.

[11]  M. Bader,et al.  Prorenin and its ancient receptor. , 2006, Hypertension.

[12]  J. D. den Dunnen,et al.  Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II , 2006, Hypertension.

[13]  E. Park,et al.  Binding properties of rat prorenin and renin to the recombinant rat renin/prorenin receptor prepared by a baculovirus expression system. , 2006, International journal of molecular medicine.

[14]  A. Nishiyama,et al.  Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage. , 2006, Journal of the American Society of Nephrology : JASN.

[15]  A. Nishiyama,et al.  Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. , 2006, Journal of the American Society of Nephrology : JASN.

[16]  K. Tsubota,et al.  Suppression of ocular inflammation in endotoxin-induced uveitis by inhibiting nonproteolytic activation of prorenin. , 2006, Investigative ophthalmology & visual science.

[17]  A. Nishiyama,et al.  Nonproteolytic Activation of Prorenin Contributes to Development of Cardiac Fibrosis in Genetic Hypertension , 2006, Hypertension.

[18]  F. Luft,et al.  Direct renin inhibition with aliskiren in hypertension and target organ damage. , 2006, Clinical journal of the American Society of Nephrology : CJASN.

[19]  Ling Yu,et al.  Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. , 2006, Kidney international.

[20]  M. Wellner,et al.  Complement Activation in Angiotensin II–Induced Organ Damage , 2005, Circulation research.

[21]  M. Wellner,et al.  Aliskiren, a Human Renin Inhibitor, Ameliorates Cardiac and Renal Damage in Double-Transgenic Rats , 2005, Hypertension.

[22]  J. Ménard,et al.  Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats , 2005, Journal of hypertension.

[23]  A. Nishiyama,et al.  Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. , 2004, The Journal of clinical investigation.

[24]  A. Ebihara,et al.  Human Prorenin Has “Gate and Handle” Regions for Its Non-proteolytic Activation* , 2003, Journal of Biological Chemistry.

[25]  G. Nguyen,et al.  Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. , 2002, The Journal of clinical investigation.

[26]  D. Ganten,et al.  Blood pressure-independent effects in rats with human renin and angiotensinogen genes. , 2000, Hypertension.

[27]  J. Ménard,et al.  Local angiotensin II generation in the rat heart: role of renin uptake. , 1998, Circulation research.

[28]  A. Danser,et al.  Mannose 6-phosphate receptor-mediated internalization and activation of prorenin by cardiac cells. , 1997, Hypertension.

[29]  D. Ganten,et al.  Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Wilson,et al.  Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. , 1990, The New England journal of medicine.

[31]  D. Wilson,et al.  Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. , 1985, The New England journal of medicine.

[32]  W. Hsueh,et al.  A comparison of cold and acid activation of big renin and of inactive renin in normal plasma. , 1978, The Journal of clinical endocrinology and metabolism.

[33]  F. Luft,et al.  An extrarenal source of "renin-like" activity in anephric man. , 1977 .

[34]  J. Laragh,et al.  Plasma prorenin: cryoactivation and relationship to renin substrate in normal subjects. , 1976, The American journal of medicine.