Angiotensin Receptor Regulation By Upstream Short Open Reading Frames

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DESCRIPTION (provided by applicant): Angiotensin II (Ang II) plays a key role in fluid homeostasis and blood pressure (BP). We have recently found that a seven amino acid peptide (PEP7) encoded within a short open reading frame in exon 2 of the 5' leader sequence of the angiotensin type 1a receptor (AT1aR) mRNA inhibits Ang II activation of extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and regulates AT1aR trafficking in cells. PEP7 also markedly reduced Ang II-mediated sodium intake without having any effect on Ang II-mediated water intake and it antagonized Ang II- induced increases in BP. Aim 1 will determine the signaling mechanism by which PEP7 inhibits Erk1/2 activation. We will test the hypothesis that PEP7 inhibition of Erk1/2 activation is Ang II dependent and mediated via the AT1aR-G protein-independent ß-arrestin signaling pathway. We will also investigate PEP7 regulation of AT1aR vesicular trafficking by inhibiting AT1aR coupling to the ß-arrestin pathway using both pharmacological and molecular approaches, and confocal microscopy. Aim 2 will elucidate the mechanism by which PEP7 regulates fluid and electrolyte homeostasis. We will investigate PEP7 effects in vivo in pathophysiological models of elevated sodium intake including hyponatremic hypovolemia and isotonic hypovolemia as well as conditions that modulate central oxytocin and vasopressin pathways and those that selectively inhibit G protein-mediated protein kinase C and G protein-independent Erk1/2 signaling cascades. Aim 3 will determine if the antihypertensive effects of PEP7 are Ang II-dependent by investigating PEP7 effects on arterial pressure in models of Ang II- and catecholamine- dependent hypertension. We will also determine if PEP7 is effective at lowering BP in two models of salt-sensitivity and what role reduced sodium intake plays in these effects. By achieving these aims, we will gain insight into PEP7 biology that could be leveraged toward developing novel interventions for diseases that are worsened by dietary sodium, like salt- sensitive hypertension.