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Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the \u03b2-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication. Here, we explored the effects of TRV and associated \u03b2-arrestin signaling in podocytes, essential cells of the kidney filter. We used human podocyte cell lines to determine \u03b2-arrestin\u2019s involvement in calcium signaling and cytoskeletal reorganization and Dahl SS rats to investigate the chronic effects of TRV administration on glomerular health. Our experiments indicate that the TRV-activated \u03b2-arrestin pathway promotes the rapid elevation of intracellular Ca2+ in a dose-dependent manner. Interestingly, the amplitude of \u03b2-arrestin-mediated Ca2+ influx was significantly higher than the response to similar Ang II concentrations. Single-channel analyses show rapid activation of transient receptor potential canonical (TRPC) channels following acute TRV application. Furthermore, the pharmacological blockade of TRPC6 significantly attenuated the \u03b2-arrestin-mediated Ca2+ influx. Additionally, prolonged activation of the \u03b2-arrestin pathway in podocytes resulted in pathological actin cytoskeleton rearrangements, higher apoptotic cell markers, and augmented glomerular damage. TRV-activated \u03b2-arrestin signaling in podocytes may promote TRPC6 channel-mediated Ca2+ influx, foot process effacement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment requires further investigation to assess the balance of the benefits versus possible deleterious effects and off-target damage.<\/jats:p>","DOI":"10.1042\/cs20230313","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T14:54:32Z","timestamp":1701788072000},"page":"1789-1804","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["\u03b2-Arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage"],"prefix":"10.1042","volume":"137","author":[{"given":"Marharyta","family":"Semenikhina","sequence":"first","affiliation":[{"name":"1Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mykhailo","family":"Fedoriuk","sequence":"additional","affiliation":[{"name":"1Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariia","family":"Stefanenko","sequence":"additional","affiliation":[{"name":"1Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine\u00a0A.","family":"Klemens","sequence":"additional","affiliation":[{"name":"2Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, U.S.A."},{"name":"3Hypertension and Kidney Research Center, University of South Florida, Tampa, FL, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alena","family":"Cherezova","sequence":"additional","affiliation":[{"name":"4Department of Physiology, Medical College of Georgia, Augusta University, GA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan","family":"Marshall","sequence":"additional","affiliation":[{"name":"5Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, GA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gentzon","family":"Hall","sequence":"additional","affiliation":[{"name":"6Division of Nephrology, Department of Internal Medicine, Duke University School of Medicine, Durham, NC, U.S.A."},{"name":"7Duke Molecular Physiology Institute, Duke University, Durham, NC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladislav","family":"Levchenko","sequence":"additional","affiliation":[{"name":"2Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashish K.","family":"Solanki","sequence":"additional","affiliation":[{"name":"1Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua\u00a0H.","family":"Lipschutz","sequence":"additional","affiliation":[{"name":"1Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"8Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4832-4170","authenticated-orcid":false,"given":"Daria\u00a0V.","family":"Ilatovskaya","sequence":"additional","affiliation":[{"name":"4Department of Physiology, Medical College of Georgia, Augusta University, GA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Staruschenko","sequence":"additional","affiliation":[{"name":"2Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, U.S.A."},{"name":"3Hypertension and Kidney Research Center, University of South Florida, Tampa, FL, U.S.A."},{"name":"9James A. Haley Veterans' Hospital, Tampa, FL, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3680-5527","authenticated-orcid":false,"given":"Oleg","family":"Palygin","sequence":"additional","affiliation":[{"name":"1Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"10Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"key":"2023122108472950300_B1","first-page":"3140","article-title":"Angiotensin-II receptor antagonists: their place in therapy","volume":"59","author":"Kirk","year":"1999","journal-title":"Am. Fam. 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