Abstract: FR-PO155
Intravenous UNI-494 Slows the Progression or Halts/Reverses AKI When Administered after Ischemia-Reperfusion in Rats
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Medicherla, Satya, Unicycive Therapeutics Inc, Los Altos, California, United States
- Reddy, Guru, Unicycive Therapeutics Inc, Los Altos, California, United States
- Gupta, Shalabh, Unicycive Therapeutics Inc, Los Altos, California, United States
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.