{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T11:02:19Z","timestamp":1793444539882,"version":"4.5.0"},"reference-count":80,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T00:00:00Z","timestamp":1689897600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Increased endothelin\u20101 (ET\u20101) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin\u2010Angiotensin\u2010Aldosterone\u2010System, modulates inflammation and vascular reactivity, partly through increased ET\u20101 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET\u20101 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156\u2009mg\/Kg), for 14\u2009days. We found that MRA treatment reduced ET\u20101 plasma levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.04), improved red cell density gradient profile (D\n                    <jats:sub>50<\/jats:sub>\n                    ;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.002), and increased mean corpuscular volume in both erythrocytes (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.02) and reticulocytes (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.024). MRA treatment also reduced the activity of the erythroid intermediate\u2010conductance Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010activated K\n                    <jats:sup>+<\/jats:sup>\n                    channel \u2013 K\n                    <jats:sub>Ca<\/jats:sub>\n                    3.1 (Gardos channel,\n                    <jats:italic>KCNN4<\/jats:italic>\n                    ), reduced cardiac levels of mRNAs encoding ET\u20101, Tumor Necrosis Factor Receptor\u20101, and protein disulfide isomerase (PDI) (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.01), and decreased plasma PDI and myeloperoxidase activity. Aldosterone (10\n                    <jats:sup>\u22128<\/jats:sup>\n                    \u2009M for 24\u2009h in vitro) also increased PDI mRNA levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.01) and activity (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.003) in EA.hy926 human endothelial cells, in a manner blocked by pre\u2010incubation with the MRA canrenoic acid (1\u2009\u03bcM;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.001). Our results suggest a novel role for MR activation in SCD that may exacerbate SCD pathophysiology and clinical complications.\n                  <\/jats:p>","DOI":"10.1096\/fj.202300671r","type":"journal-article","created":{"date-parts":[[2023,7,22]],"date-time":"2023-07-22T01:24:34Z","timestamp":1689989074000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Blockade of the mineralocorticoid receptor improves markers of human endothelial cell dysfunction and hematological indices in a mouse model of sickle cell disease"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0433-6367","authenticated-orcid":false,"given":"Alicia","family":"Rivera","sequence":"first","affiliation":[{"name":"Division of Nephrology, Vascular Biology Research Center, Department of Medicine, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"},{"name":"Departments of Laboratory Medicine and Pathology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Vega","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arelys","family":"Ramos\u2010Rivera","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique R.","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory N.","family":"Prado","sequence":"additional","affiliation":[{"name":"Departments of Laboratory Medicine and Pathology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Endocrinology, Diabetes and Hypertension, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hope E.","family":"Karnes","sequence":"additional","affiliation":[{"name":"Quest Diagnostics  Secaucus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri A.","family":"Fesko","sequence":"additional","affiliation":[{"name":"Quest Diagnostics  Secaucus New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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