title: Selective inhibition of angiotensin receptor signaling through Erk1/2 pathway by a novel peptide.
abstract: A seven-amino acid peptide (PEP7) is encoded within a short open reading frame within exon 2 (E2) in the 5'-leader sequence (5'LS) upstream of the rat ANG 1a-receptor (rAT1aR) mRNA. A chemically synthesized PEP7 markedly inhibited ANG II-induced Erk1/2 activation in cell culture by 62% compared with a scrambled PEP7 (sPEP7) [pErk1/2/Erk1/2 (AU): ANG II, 1.000 ± 0.0, ANG II+PEP7, 0.3812 ± 0.086, ANG II+sPEP7, 1.069 ± 0.18; n = 3]. Under these same conditions, PEP7 had no effect on ANG II-stimulated inositol-trisphosphate production. PEP7 also had no effect on epidermal growth factor- and phorbol methyl ester-induced Erk1/2 activation, suggesting PEP7 selectively inhibits AT1aR-mediated Erk1/2 signaling. PEP7 intracerebroventricularly inhibited ANG II-induced saline intake but had no effect on water intake in male and female rats, indicating PEP7 also selectively inhibits the ANG II-Erk1/2 pathway in vivo since saline drinking is Erk1/2-mediated, while water drinking is not. PEP7 inhibition of ANG II-induced saline ingestion was rapidly reversed by a subsequent intracerebroventricular injection of an oxytocin antagonist, suggesting when PEP7 blocks ANG II-stimulated Erk1/2 activation, animals no longer ingest saline to balance the continued water intake, due to the release of oxytocin and its subsequent inhibitory effects on saline drinking. PEP7 also attenuated ANG II-induced increases in arterial pressure by 35% compared with sPEP7 at the same dose. Thus, we have identified a novel peptide encoded within the rAT1aR E2 that selectively inhibits Erk1/2 activation, resulting in physiological consequences for sodium ingestion and arterial pressure that may have implications for treating sodium-sensitive diseases like hypertension and chronic kidney disease.
authors: Division of Nephrology and Hypertension, Department of Medicine, Georgetown University, Washington, D.C.;
authors: Jun
authors: J
authors: Liu
authors: Gina L C
authors: GL
authors: Yosten
authors: Hong
authors: H
authors: Ji
authors: Dan
authors: D
authors: Zhang
authors: Wei
authors: W
authors: Zheng
authors: Robert C
authors: RC
authors: Speth
authors: Willis K
authors: WK
authors: Samson
authors: Kathryn
authors: K
authors: Sandberg
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004326:Drinking / Q000187:drug effects; D005260:Female; D006973:Hypertension / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D011945:Receptors, Angiotensin; D000804:Angiotensin II
keywords: Erk1/2; PEP7; angiotensin II; angiotensin receptor; sodium intake