Fisetin attenuates renal ischemia/reperfusion injury by improving mitochondrial quality, reducing apoptosis and oxidative stress.

Renal ischemic reperfusion (IR) injury is one of the major source of mortality and morbidity associated with acute kidney injury (AKI). Several flavonoids have shown to be renal protective against many nephrotoxic agents causing AKI. Fisetin, a promising flavonoid, is effective in the management of septic AKI, expected to ameliorate renal IR injury. The present study aimed to generate evidence for fisetin-mediated renal protection against IR injury. Male Wistar rats of 200-250 g were subjected to IR protocol by performing bilateral clamping for 45 min and reperfusion for 24 h. Fisetin was administrated 30 min (20 mg/kg b.wt, ip) before the surgery. Renal injury was evaluated by measuring the biomarkers in plasma, examining the ultra-structure of the kidney, and analyzing the apoptotic changes. Oxidative stress, antioxidant levels, and mitochondrial function were analyzed in the renal tissue. Fisetin administration significantly reduced the renal damages associated with IR by improving estimated glomerular filtration rate (eGFR: IR-0.35 ml/min, F_IR-9.03 ml/min), reducing plasma creatinine level (IR-2.2 mg/dl, F_IR-0.92 mg/dl), and lowering urinary albumin/creatinine ratio (IR-6.09 F_IR-2.16), caspase activity, decreased DNA fragmentation and reduced tubular injury score (IR- 11 F_IR-6.5). At the cellular level, fisetin significantly reduced renal oxidative stress and augmented the antioxidant levels. Fisetin was found to preserve mitochondrial electron transport chain activities and improved the ATP producing capacity in the renal tissue upon IR injury. Fisetin pretreatment attenuates renal IR injury by improving renal function, reducing the renal injury mediated by apoptosis, reducing free radical release, and augmenting mitochondrial function.