Susceptibility of both female and male mice to acute kidney injury (AKI): protective effect of P2Y14 receptor inhibition

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While sex is increasingly considered as a critical variable in kidney health, female mice and patients remain underrepresented in preclinical and clinical studies. Ischemic-induced AKI is a frequent complication in hospitalized patients. Here, we assessed the severity of AKI in female and male C57BL/CBAF1mice subjected to bilateral ischemia-reperfusion injury (BIRI), with a clamping time of 35 min and reperfusion for 24 h (n ≥ 8 mice per group). SHAM surgeries were performed without clamping. Based on plasma creatinine (pCre), females showed an apparent AKI protection versus males (females: fold increase of pCre-BIRI/SHAM = 1.6, p=0.18, versus males: pCre-BIRI/SHAM = 7.8, p=0.005). BIRI induced a 2.8-fold increase in blood urea nitrogen (BUN) versus SHAM in females (p=0.04), and a 5.2-fold increase in males (p<0.001). A significant increase in the percentage of severely damaged proximal tubules (PTs), characterized by a complete loss of AQP1 polarity, was observed in both females (61% BIRI vs 0% SHAM, p = 0.03) and males (45% BIRI vs 0% SHAM, p = 0.001). WB showed an increase in the expression of acyl-CoA synthetase long-chain family member 4 (ASCL4), indicating induction of ferroptosis by BIRI, in females and males. We previously showed that the pro-inflammatory P2Y14 receptor is a key driver of AKI in male mice. Here, both females and males treated with the P2Y14 antagonist, PPTN, showed reduced severity of BIRI-induced AKI versus the non-treated group, as evidenced by: 1) reduced BUN elevation (BIRI-PPTN = 7.82 mmol/L versus BIRI-vehicle = 16.02 mmol/L, p=0.03 in females, and BIRI-PPTN = 18.22 mmol/L versus BIRI-vehicle = 33.62, p=0.05 in males); 2) reduction in the percentage of damaged PTs (BIRI-PPTN = 1.1%, p=0.002 versus BIRI-vehicle in females, and BIRI-PPTN= 16.4%, p=0.03 versus BIRI-vehicle in males); 3) expression of ASCL4 similar to that of SHAM levels in females and males. Interestingly, a lower dose of PPTN was required in females (5 mg/kg/day) versus males (10 mg/kg/day) to achieve maximal response. In addition, preliminary results showed a BIRI-induced increase in Ly6G positive neutrophils in kidney sections from males and females, and reduction of neutrophil numbers upon PPTN treatment. We are currently analyzing, by LC-MS/MS, the renal expression of lipids potentially involved in the inflammatory response (prostaglandins, leukotrienes, endocannabinoids and their congeners) after BIRI with and without PPTN treatment. Overall, our results show that both females and males can develop ischemic-AKI, and that pCre is a poor marker of AKI in females. Finally, this study shows that attenuation of renal inflammation via P2Y14 inhibition protects against ferroptosis and reduces the extent of kidney dysfunction and damage following ischemia-reperfusion injury in both female and male mice. CIHR PJT-183711-2022 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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