Intravenous UNI-494 Slows the Progression or Halts/Reverses AKI When Administered after Ischemia-Reperfusion in Rats

Background: There are no effective treatments approved for 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 originating from ischemia-reperfusion (I/R) injury or delayed graft function (DGF). Unresolved inflammation exacerbates sustained mPTP opening, evident in chronic kidney diseases. UNI-494, a selective mitochondrial ATP-sensitive potassium channel activator, reverses mitochondrial dysfunction by closing the mPTP. We evaluated in vivo efficacy of intravenous (IV) UNI-494 administered therapeutically after unilateral I/R in AKI rat model. Methods: Rats were anesthetized, right kidney removed, I/R induced by clamping renal vessels in left kidney (30 minutes). After 1 or 4 hours of reperfusion with established renal injury confirmed by elevated serum creatinine (sCr), 10 mg/kg of UNI-494 was administered IV. After 24 hours reperfusion in metabolic cages, blood samples were collected for sCr and blood urea nitrogen (sBUN) levels, and urinary samples collected for albumin-creatinine ratio (uACR) and neutrophil gelatinase-associated lipocalin (uNGAL). At necropsy, clamped left kidney was collected and processed for histology for tubular injury scores. Results: I/R induced significant increases of sCr, sBUN, uACR, uNGAL, and proximal convoluted tubular injury scores in vehicle treated I/R group vs No I/R sham group. A single IV dose of 10 mg/kg of UNI-494 improved kidney functional markers sCr, sBUN, uACR, uNGAL, and proximal tubular injury scores (Figure 1). Conclusion: Single IV doses of 10 mg/kg of UNI-494 administered after I/R significantly reduced serum and urinary AKI markers and improved proximal tubular injury scores. These data indicate therapeutic administration of UNI-494 slows down, or even halts/reverses, AKI progression. UNI-494 is a potential candidate for prevention of DGF and other AKI clinical conditions. Funding: Commercial Support - Unicycive Therapeutics, Inc.