EC Pharmacology And Toxicology

Background: There are no FDA approved drugs for the treatment of acute kidney injury (AKI). Inflammation- and reactive oxygen species-driven mitochondrial permeability transition pore (mPTP) opening causes mitochondrial dysfunction/swelling and cell death. This is implicated in acute diseases including AKI originating from ischemia-reperfusion (I/R) injury or delayed graft function. Additionally, unresolved inflammation exacerbates sustained mPTP opening and induces fibrotic lesions, evident in chronic kidney diseases. Nicotinamide adenine dinucleotide can suppress the frequency and duration of mPTP opening. UNI-494, a novel nicotinamide ester derivative and a selective mitochondrial ATP-sensitive potassium channel activator, reverses mitochondrial dysfunction by closing the mPTP. We present results from a study evaluating UNI-494's efficacy in treating AKI in an I/R AKI rat model.

Methods: 48 Sprague-Dawley rats were randomly assigned to 4 groups: one sham group and three I/R models. Rats were anesthetized, the right kidney was removed, and I/R was induced in the left kidney. I/R models received either no treatment or UNI-494 IV at 1 hour or 4 hours after ischemia. Blood and urinary samples were collected for AKI markers. The clamped left kidney was collected for tubular injury scores.

Results: UNI-494 at 10 mg/kg/IV reduced AKI markers and tubular injury scores in an AKI rat model compared to vehicle treated I/R group.

Conclusion: A single IV dose of UNI-494 at 10 mg/kg at 1 or 4 hours after ischemia significantly reduced the kidney functional markers and tubular injury scores. The data suggest UNI-494 slows down/reverses the progression of AKI in its established state.

 Keywords: Acute Kidney Injury; UNI-494; Ischemia-Reperfusion; Acute Kidney Injury Treatment; Efficacy

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