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Thirty minutes later, ischemia was induced in the left kidney by clamping its artery and vein for 45\u00a0min. Rats were then transferred to metabolic cages for 24-h urine collection, and blood was taken at the 24-h time point. Renal function (blood urea nitrogen [BUN], serum creatinine [SCr], and creatinine clearance [CCr]) and 23 serum cytokines were assessed, along with histopathological evaluation of renal tubular damage.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Compared with the sham group, the vehicle group showed increased BUN and SCr levels, reduced CCr, and renal tubular damage. Difelikefalin improved BUN, SCr, and CCr levels and mitigated renal tubular damage. Similar effects were observed with nalfurafine hydrochloride and U-50488H. Thirteen serum cytokines were elevated in the vehicle group. Difelikefalin suppressed all elevated cytokines, U-50488H showed moderate efficacy, and nalfurafine hydrochloride exhibited little inhibitory effect.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These findings indicate that difelikefalin has anti-inflammatory and renoprotective effects in a rat acute kidney injury model, with varying anti-inflammatory efficacy among KOR agonists.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12882-025-04199-9","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T09:40:10Z","timestamp":1751362810000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Anti-inflammatory and renoprotective effects of difelikefalin, a kappa opioid receptor agonist, in a rat model of renal ischemia\u2013reperfusion-induced acute kidney injury"],"prefix":"10.1186","volume":"26","author":[{"given":"Hiroto","family":"Takeuchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tatemichi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Okuhara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"issue":"5","key":"4199_CR1","first-page":"643","volume":"25","author":"SS Hashemi","year":"2022","unstructured":"Hashemi SS, Janfeshan S, Karimi Z. 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The study was approved by the Laboratory Animal Care and Use Committee of the Central Research Laboratories of Kissei Pharmaceutical Co., Ltd. (Committee approval numbers: 22A-006, 22B-043). The general condition of the animals was carefully monitored at least once a day to assess pain and distress. If serious signs of pain and distress had been observed\u2014such as reduced reflexes, ataxic gait, or low body temperature\u2014the affected animal would have been euthanized. All experimental procedures were performed with care to minimize pain and distress in the animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"307"}}