{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:40:23Z","timestamp":1776796823331,"version":"3.51.2"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Maruishi Pharmaceutical Co., Ltd."},{"name":"JSPS KAKENHI","award":["20K17867"],"award-info":[{"award-number":["20K17867"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>There is a pressing need for therapies that can lessen the severity of acute kidney injury (AKI) and subsequent critical illness. Difelikefalin, a peripherally acting kappa opioid receptor agonist, shows promise in controlling postoperative pain and chronic kidney disease-associated pruritis. Here, we report that difelikefalin attenuated AKI in experimental mouse models of critical illness. Preconditioning with difelikefalin significantly reduced oliguria in both lipopolysaccharide (LPS)-induced and cecum ligation and puncture-induced models. Moreover, difelikefalin treatment after renal ischemia\/reperfusion substantially decreased the LPS-induced mortality rate on day 6 post-ischemia\/reperfusion. We hypothesized that the reno-protective effects of difelikefalin are mediated through receptors expressed in either the neural system, immune cells, or the renal parenchyma. Denervation of nerves around the renal pedicle improved urine flow; difelikefalin further enhanced this improvement, regardless of renal denervation. Difelikefalin did not affect plasma cytokine levels after LPS administration at 3 and 6 hours. Renal kappa receptor expression overlapped with the pattern of neural crest-derived interstitial cells. LPS administration tended to increase cytokine expression in isolated renal kappa receptor-positive cells, and difelikefalin suppressed these changes. Overall, difelikefalin demonstrated renal protective effects against AKI in murine endotoxemia and polymicrobial sepsis models and improved survival in post-ischemia\/reperfusion endotoxemia.<\/jats:p>","DOI":"10.1371\/journal.pone.0343693","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T17:45:13Z","timestamp":1776793513000},"page":"e0343693","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A kappa opioid receptor agonist, difelikefalin, improves acute kidney injury in experimental sepsis models"],"prefix":"10.1371","volume":"21","author":[{"given":"Yoshiharu","family":"Sawanobori","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7435-8465","authenticated-orcid":true,"given":"Daisuke","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Kitamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kento","family":"Kitada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehiko","family":"Asaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Ogino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gotaro","family":"Shirakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Nishiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"issue":"5","key":"pone.0343693.ref001","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1213\/ANE.0000000000003741","article-title":"Update 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