Identification of the H+-K+-ATPase ATP4A as hypoxia-regulated target for acute kidney injury prevention

Acute kidney injury (AKI) is the most common disease in critically ill patients and it is an important factor in the increase of morbidity and mortality yet the therapeutic strategy for AKI prevention is not established. Hypoxia Inducible Factors (HIFs) have been studied that play an important role during AKI to reduce its severity. Here we investigated to identify the novel therapeutic target of HIF2A during ischemic AKI. We performed microarray with the vechle- or PT2385 (HIF2A specific inhibitor) to find the downstream gene of Hif2a and identified that H+-K+-ATPase Atp4a was a leading candidate of HIF2A targeted gene which was suppressed by HIF2A in the tubular epithelial cell. We further uncovered that pharmacological inhibition of Atp4a or genetic deletion of Atp4a reduced AKI during renal ischemia and reperfusion. Mice were performed with 30 minutes of ischemia and 24 hours of reperfusion for vehicle- or PT2385 treated (10 mg/kg of PT2384 was injecteed at 16 hours before surgery, 1 hour, 8 hours and 20 hours after surgery) mice .Rnal tubular epithelial cells were isolated from the kidney.