The recently defined necroptosis process participates in the pathophysiology of several tissue injuries. Targeting the necroptosis mediator receptor-interacting protein kinase (RIPK1) by necrostatin-1 in different phases of ischemia-reperfusion injury (IRI) may provide new insight into the protection against renal IRI. The rat groups included (n= 8 in each group); 1) Sham, 2) Renal IRI, 3) Necrostatin-1 treatment 20 min before ischemia induction in a dose of 1.65 mg/kg/intravenous. 4) Necrostatin-1 injection just before reperfusion, 5) Necrostatin-1 injection 20 min after reperfusion establishment, and 6) drug injection at both the pre-ischemia and at reperfusion time in the same dose. Timing dependent, necrostatin-1 diminished RIPK1 (P < 0.001), and aborted the necroptosis induced renal cell injury. Necrostatin-1 decreased the renal chemokine (CXCL1), interleukin-6, intercellular adhesion molecule (ICAM-1), myeloperoxidase, and the nuclear factor (NFκB), concomitant with reduced inducible nitric oxide synthase (iNOS), inflammatory cell infiltration, and diminished cell death represented by apoptotic cell count and the BAX/Bcl2 protein ratio. In group six, the cell injury was minimum and the renal functions (creatinine, BUN, and creatinine clearance) were almost normalized. The inflammatory markers were diminished (P < 0.001) compared to the IRI group. The results were confirmed by histopathological examination. In conclusion, RIPK1 inhibition ameliorates the inflammatory immune response induced by renal IRI. The use of two doses was more beneficial as the pathophysiology of cell injury is characterized.
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