Anti-inflammatory and renoprotective effects of difelikefalin, a kappa opioid receptor agonist, in a rat model of renal ischemia-reperfusion-induced acute kidney injury.

BACKGROUND: This study evaluated the effects of difelikefalin, a kappa opioid receptor (KOR) agonist, on the inflammatory response and renal dysfunction in a rat model of acute kidney injury induced by renal ischemia-reperfusion injury, comparing it with other KOR agonists. METHODS: One week after right nephrectomy, rats received one of three drugs (difelikefalin, nalfurafine hydrochloride, or U-50488H). Thirty minutes later, ischemia was induced in the left kidney by clamping its artery and vein for 45 min. 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. RESULTS: 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. CONCLUSION: 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.