Vitexin alleviates renal ischemia/reperfusion injury in rats via activation of Nrf2 and inhibition of necroptosis pathways

Abstract

Background Renal ischemia/reperfusion injury is a frequent kidney condition caused by various conditions like kidney and heart surgery. Renal ischemia causes cellular damage and death, whereas reperfusion reintroduces blood into the kidney but generates inflammatory reactions and cellular damage, worsening kidney injury. Vitexin is present in the leaves and other various parts of several medicinal plants. It has excellent safety and pleiotropic effects in oxidation, inflammation, cancer, infection, and neuro-cardio-hepatoprotection. According to our knowledge, there is limited data about the nephroprotective effects of vitexin on renal ischemia/reperfusion injury-induced acute kidney injury. Therefore, this study seeks to assess the nephroprotective effects of vitexin through Nrf2 and RIPK1/MLKL molecular pathways.

Materials and methods Twenty-four Sprague Dawley rats were allocated into four groups: The sham group was subjected to laparotomy without the I/R induction. The I/R, I/R+Veh, and I/R+VTN groups were exposed to 30 minutes of bilateral renal ischemia, which was followed by 24 hours of reperfusion. The I/R+Veh and I/R+VTN groups administered DMSO and 40 mg/kg of vitexin by the I. P. route one hour before the I/R induction, respectively. Renal damage marker (KIM-1), inflammatory markers (TNF-α, IL-1β, and NF-κB), and apoptotic marker (caspase-3) were measured by ELISA. Nrf2 and MLKL were assessed by IHC, and RIPK1 was analyzed by RT-qPCR, in addition to histopathological examination.

Results The control and vehicle groups showed substantial elevation of KIM-1, NF-κB, TNF-α, IL-1β, caspase-3, RIPK1, MLKL, and histopathological findings. Conversely, vitexin displayed a remarkable reduction in renal damage, inflammatory markers, cellular death, and histopathological findings. In the vitexin-treated group, nuclear translocation of Nrf2 was markedly escalated. Moreover, molecular docking showed that vitexin interacted with Keap1. 

Conclusion The present study confirmed that vitexin had substantial nephroprotective effects against renal IRI. Vitexin diminished inflammation, necroptosis, apoptosis, and necrosis through activation of Nrf2 and inhibition of RIPK1/MLKL pathways.