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 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 drinking and it antagonized Ang II-induced increases in BP. Recognizing that with aging come significant changes in thirst, urinary concentrating ability and the ability to excrete water and electrolytes, we determined if aging alters the ratio of expression of the two splice variants of the AT1aR [one that encodes PEP7 (E-1,2,3-AT1aR) and the other that does not (E-1,3-AT1aR)] and found, indeed, that young animals express a higher ratio of E-1,2,3-AT1aR/E-1,3-AT1aR than aged animals. We also observed that aging affects the density of AT1R binding in adrenal gland. Thus changes in the expression of PEP7 (present in higher levels in young compared to older animals because of changes changes in E-1,2,3- and E-1,3-AT1aR expression) may lead to impaired AT1R regulation in response to environmental changes in electrolyte balance. Studies proposed in this application (supplement to our funded grant HL121456) address the hypothesis that the ratio of the expression of the splice variants of the AT1aR changes with aging, favoring the E-1,3-AT1aR, resulting in less PEP7 production, and contributing to age-associated impairments in fluid and electrolyte homeostasis and blood pressure. We will determine if supplementation with PEP7 in aged animals returns their fluid homeostasis to normal and if reduction in PEP7 production in young animals precipitates the aged phenotype. Renin-angiotensin system dysfunction is associated with diverse pathologies associated with aging. Therefore, these studies may lead to novel therapeutic approaches for the treatment of age-related alterations in fluid homeostasis and cardiovascular function.