TRPC6 deficiency attenuates renal injury and mitochondrial dysfunction in ischemia/reperfusion-induced acute kidney injury

Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is a major clinical problem without effective therapy and is a significant cause of morbidity and mortality during the perioperative period. The hallmarks of I/R-AKI include renal tubular cell injury and mitochondrial dysfunction. Transient receptor potential channel subfamily C member 6 (TRPC6), a non-selective cation channel that mediates the influx of calcium and other monovalent cations into cells, is widely expressed in the kidney, including proximal tubular cells. TRPC6 deficiency has been reported to be protective in chronic kidney diseases by reducing oxidative stress; however, its role in AKI is still controversial. In this study, we examined the role of TRPC6 during the early phase of renal injury in I/R-induced AKI. To reduce the severity and limit variability in kidney injury after I/R, we performed unilateral I/R surgery with 30 minutes of ischemia in the left kidney of 22-week-old male wild-type (WT) and whole-body TRPC6 knockout (TRPC6 KO) mice. Mitochondrial respiration rate and mitochondria-generated superoxide in the left kidney were examined 18 hours after I/R surgery by OROBOROS Oxygraph Respirometry. Serum creatinine and urinary neutrophil gelatinase-associated lipocalin (NGAL) concentration were determined in addition to histological evaluation by PAS staining in WT and TRPC6 KO mice. Our results show that the mitochondrial oxygen consumption rate was significantly higher in I/R kidneys from TRPC6 KO mice compared to WT (56.5±9.3 vs. 22.9±2.0 pmol/min/mg, n=5-6). Despite higher mitochondrial respiration, mitochondria-generated superoxide production was significantly lower in the kidney of TRPC6 KO mice. TRPC6 KO mice also exhibited significantly lower serum creatinine (0.26±0.02 vs. 0.37±0.08 mg/dL, n=7-10) and urinary NGAL levels (526.6±58.7 vs. 1313.5±192.0 ng/mL, n=6-10) than WT mice. Renal histology showed that I/R kidneys from TRPC6 KO mice have reduced tubular cell death in outer medulla areas and decreased tubular clots and inflammatory cell infiltration. These observations suggest that TRPC6 deficiency may be protective during the early phase of I/R-induced AKI by preserving mitochondrial respiration and attenuating mitochondria reactive oxygen species generation. Targeting TRPC6 and its downstream signaling pathways may provide new avenues for future I/R-induced AKI therapies. (NIDDK R00DK113280 and R01DK121411, NIGMS P20GM104357 and NIGMS U54GM115428) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.