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The Putative (Pro)renin Receptor Blocker HRP Fails to Prevent (Pro)renin Signaling

Sandra Feldt^*, Ulrike Maschke, Ralf Dechend^*, Friedrich C. Luft^*, and Dominik N. Muller^*,

^* Medical Faculty of the Charité, Experimental and Clinical Research Center, Franz Volhard Clinic, and HELIOS Klinikum Berlin-Buch, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany

Correspondence: Dr. Dominik N. Muller, Experimental and Clinical Research Center, Max-Delbruck-Center, Lindenberger Weg 80, 13125 Berlin, Germany. Phone: +49-30-9406-4581; Fax: +49-30-9406-4220; E-mail: dominik.mueller{at}mdc-berlin.de

Received for publication September 23, 2007. Accepted for publication November 22, 2007.

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.

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