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.
Feldt
Sandra
S
Experimental and Clinical Research Center, Max-Delbruck-Center, Lindenberger Weg 80, 13125 Berlin, Germany.
Maschke
Ulrike
U
Dechend
Ralf
R
Luft
Friedrich C
FC
Muller
Dominik N
DN
D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012083:Renin / Q000187:drug effects* / Q000502:physiology; D000092502:Renin Inhibitors
D000577:Amides; D000804:Angiotensin II; D005650:Fumarates; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C527127:handle-region peptide, rat; C446481:aliskiren