{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T19:34:12Z","timestamp":1778700852043,"version":"3.51.4"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27\u00a0days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26\u00a0days of treatment. Serum K<jats:sup>+<\/jats:sup> was evaluated after 14 and 27\u00a0days of treatment. Urinary Na<jats:sup>+<\/jats:sup>, urinary K<jats:sup>+<\/jats:sup>, and urinary Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup> ratio were evaluated after 7, 14, and 26\u00a0days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC<jats:sub>50<\/jats:sub>) for increasing serum K<jats:sup>+<\/jats:sup> to the EC<jats:sub>50<\/jats:sub> for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K<jats:sup>+<\/jats:sup>, and decreased urinary Na<jats:sup>+<\/jats:sup> relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone\/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5\u00a0mg\/kg BID while eplerenone did so only at the two highest doses of 50 and 450\u00a0mg\/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K<jats:sup>+<\/jats:sup> seen in the aldosterone treatment group, with significant increases in serum K<jats:sup>+<\/jats:sup> at the high doses only (5\u00a0mg\/kg and 450\u00a0mg\/kg BID, respectively). Additionally, the urinary Na<jats:sup>+<\/jats:sup> and Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup> ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.<\/jats:p>","DOI":"10.3389\/fphar.2021.604928","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T05:27:22Z","timestamp":1624512442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury"],"prefix":"10.3389","volume":"12","author":[{"given":"Fr\u00e9d\u00e9ric","family":"Jaisser","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojuan","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangshuang","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinrong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Bush","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Benn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. 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