{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:12:11Z","timestamp":1753884731011,"version":"3.41.2"},"reference-count":22,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The activity of the Epithelial Na<jats:sup>+<\/jats:sup> Channel (ENaC) in renal principal cells (PC) fine\u2010tunes sodium excretion and consequently affects blood pressure. G\u2010coupled receptors play an important role in regulating ENaC activity. We previously explored the role of Gq and Gs in regulating ENaC activity by using the designer receptors exclusively activated by designer drugs (DREADD) technology. We demonstrated that pharmacogenetic activation of Gq (Gq\u2010DREADD) exclusively in principal cells by Clozapine\u2010N\u2010oxide (CNO) reduced ENaC activity in renal tubules, promoting natriuresis that lowered elevated blood pressure in the DOCA\u2010salt model of hypertension. In addition, by investigating the Gs\u2010adenylyl cyclase\u2010cAMP signal transduction pathway, we exhibited that treatment of PC\u2010specific Gs\u2010DREADD mice with CNO rapidly and significantly decreased urinary Na<jats:sup>+<\/jats:sup> excretion. In this study, we investigate the role of Gi\u2010DREADD in regulating ENaC activity. Our results showed that Gi\u2010DREADD, expressed exclusively in renal principal cells, activated by CNO reduced ENaC activity and significantly increased urinary Na<jats:sup>+<\/jats:sup> excretion compared to CNO\u2010treated littermates. These findings provide for the first time that target activation of Gi signaling exclusively in PCs is sufficient to decrease ENaC activity and increase dependent urinary Na<jats:sup>+<\/jats:sup> excretion in live animals.<\/jats:p>","DOI":"10.14814\/phy2.70433","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T14:45:49Z","timestamp":1750171549000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gi\u2010<scp>DREADD<\/scp> activation decreases Epithelial Na<sup>+<\/sup> channel activity in renal principal cells"],"prefix":"10.14814","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3441-9673","authenticated-orcid":false,"given":"Tarek Mohamed","family":"Abd El\u2010Aziz","sequence":"first","affiliation":[{"name":"Zoology Department, Faculty of Science Minia University  Minya 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