Abstract
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 200-250g were subjected to IR protocol by performing bilateral clamping for 45min and reperfusion for 24h. Fisetin was administrated 30min (20mg/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-0.35ml/min, F_IR-9.03ml/min), reducing plasma creatinine level (IR-2.2mg/dl, F_IR-0.92mg/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.
Highlights
Renal insufficiency due to ischemia reperfusion (IR) is one of the major concerns of clinicians in the management of acute kidney diseases where ischemic reperfusion (IR) injury can compromise normal regulation of fluid, electrolyte and acid base homeostasis (Basile et al 2012; Ding et al 2017)
Fisetin administration significantly reduced the renal damages associated with IR, by improving estimated glomerular filtration rate, 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)
The present study aims at unravelling the reno-protective effects of fisetin and underlying mechanisms in a rat model of renal ischemia reperfusion injury
Summary
Renal insufficiency due to ischemia reperfusion (IR) is one of the major concerns of clinicians in the management of acute kidney diseases where IR injury can compromise normal regulation of fluid, electrolyte and acid base homeostasis (Basile et al 2012; Ding et al 2017). The major groups of molecules includes anti-apoptosis/necrosis agents, free radical scavengers, antisepsis, growth factors, vasodilators and anti-inflammatory agents (Jo et al 2007) These compounds showed beneficial effects in pre-clinical settings, clinical translation of its effect is questionable as the compounds look for specific targets and it is difficult to rule out other overlapping or similar effects that could have been partly responsible for causing renal injury and dysfunction (Jo et al 2007). This may be addressed by increasing the ability of the renal tissue to withstand IR or search for a multi targeted agent to tackle multifaceted IR pathology
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