In this study, it was focused on the evaluation of the effects of rutin against cisplatin-induced kidney injury with the kidney function tests (serum urea and creatinine), oxidative stress parameter (MDA), antioxidants (catalase, SOD, GSH), caspase-3, and Bcl-3 parameters. This study demonstrated the oxidative stress, increased caspase-3 and Bcl-3 levels in the kidney injury induced by cisplatin treatment. Similarly, several studies have demonstrated that the administration of cisplatin to the rats causes nephrotoxicity by elevated inflammatory markers such as NF-ĸB, TNF-α, and IL-1β and oxidative stress marker MDA levels and decreased antioxidants such as GSH levels, catalase, and SOD activities
30. In this study, single dose of 10 mg/kg cisplatin established the kidney injury determined by the kidney dysfunction as demonstrated by increased serum urea and creatinine concentrations, increased MDA levels, and increased caspase-3 levels.
In the pathogenesis of cisplatin-induced kidney injury, the mitochondrial dysfunction caused by reactive oxygen species (ROS) with increase in oxidants such as superoxide anion, hydrogen peroxide and decrease in SOD activities were noted 31,32. Another study also confirmed the role of increased ROS, and apoptotic pathway proteins such as caspase-3, NF-κB, and TNF-α in cisplatin related kidney injury 33. Similarly, another study showed that cisplatin induced the release of proinflammatory cytokines such as NF-κB, TNF-α, IL-1β, IL-6, IL-33, iNOS and COX-2 and decreased the kidney SOD, catalase and GSH-Px activities and GSH levels 34.
In this study, the increased kidney MDA levels revealed that cisplatin could cause lipid peroxidation in the kidney epithelial cells via decrease in the kidney SOD, catalase and GSH-Px activities and GSH levels, and could activate apoptotic protein pathways as revealed by increased caspase-3 levels. This suggests the activation of caspases and the induction of apoptosis. Caspases are activated by the release of cytochrome C to cytosol 35. Malik et al. 35 have showed that cisplatin causes increase in caspase expression and apoptosis in the kidney cells.
In this study, rutin pretreatment prevented significantly apoptotic protein caspase-3 increase in cisplatin plus rutin group. Thus, rutin pretreatment provided decrease in anti-apoptotic protein Bcl-3 due to alleviation of apoptosis in the kidney of cisplatin plus rutin group. This suggests that rutin has significant anti-apoptotic effects against cisplatin nephrotoxicity in the rat kidney tissue.
Several studies have demonstrated that the antioxidant compounds such as rutin 33, tangeretin 36, embelin 30, melatonin (367) prevent oxidative stress and inflammation on cisplatin-induced kidney injury.
Rutin, an active citrus flavonoid compound, exerts its effects via potent antioxidant properties. Rutin can scavenge radicals and activate intrinsic antioxidant defense systems 17,19,38.
Cisplatin can lead to the depletion of GSH and other antioxidants 34. In this study, rutin pretreatment reversed the kidney GSH depletion due to cisplatin treatment by increasing significantly GSH contents in the kidney. In addition, rutin pretreatment reversed oxidative stress induced by cisplatin as demonstrated by increased GSH levels, SOD, catalase, and GSH-Px activities, and decreased MDA levels.
B-cell lymphoma protein 3 (Bcl-3) is described as a negative regulator of transcription factor NF-ĸB 39,40. Poveda et al. 41 have revealed that Bcl-3 is upregulated in acute kidney injury and supports to block inflammatory and lethal responses related to inflammatory stimuli in tubular cells. In addition, cleaved caspase-3 is increased by Bcl-3 silencing in inflammatory condition. Accordingly, rutin pretreatment in cisplatin nephrotoxicity provided the reduction of kidney Bcl-3 levels due to alleviation of oxidative stress, the reduction of the apoptotic protein caspase-3, and increasing of GSH levels and other antioxidants such as SOD, catalase and GSH-Px activities in the rat kidneys.
This study demonstrated that rutin pretreatment given at a dose of 150 mg/kg alleviated cisplatin nephrotoxicity in the rats by decreasing serum urea and creatinine concentrations, the kidney MDA and the kidney caspase-3 levels, and by increasing the kidney SOD, catalase and GSH-Px activities, and GSH levels.