Oxytocin’s role in salt appetite revealed by PEP7 blockade of angiotensin II action (683.1)

Abstract

The paradoxical mechanism by which angiotensin II (Ang II) stimulates saline intake and simultaneously releases oxytocin (OT), which profoundly inhibits Ang II‐induced saline intake, is not known. We discovered that a 7 amino acid peptide (PEP7) encoded by a short open reading frame in the 5’ leader sequence of the angiotensin type 1a receptor (AT1aR) mRNA blocks saline, but not water, intake induced by Ang II by abrogating the non‐G protein‐coupled Erk1/2 signaling pathway. We hypothesized that blockade of the MAP‐kinase‐dependent pathway uncovers the inhibitory action of OT released in response to Ang II. Pretreatment icv with PEP7 blocks the saline intake response and this can be reversed by subsequent icv administration of the OT antagonist, OVT. Thus Ang II controls electrolyte intake via two unique pathways, one stimulatory (MAP‐kinase dependent, blockable by PEP7), and the other inhibitory (G protein‐dependent, via OT release). These results together with in vitro data demonstrating PEP7 selective inhibition of the MAP‐kinase‐dependent signaling pathway suggests that PEP7 is a novel therapeutic target for pathologies involving MAP‐kinase dependent, non‐G protein‐coupled signaling of Ang II.Grant Funding Source: NIH AG/HL 19291, HL57502, AG039779, AG16902, HL066023