Sacubitril/valsartan attenuates renal injury caused by cecal ligation and puncture via TLR4/NFκB/NLRP3 inhibition and reduced oxidative stress and apoptosis in rats

Abstract

Sepsis constitutes a life-threatening systemic inflammatory response triggered by infection. It remains among the leading causes of in-hospital mortality, claiming over 11 million lives annually. For the first time, this study aimed to evaluate the capacity of sacubitril/valsartan to protect against renal damage induced by cecal ligation and puncture (CLP) in an experimental rat model. The CLP procedure was employed to establish a rat model of sepsis. Renal oxidative stress markers including MDA, GSH, and SOD were quantified. ELISA was used to measure renal levels of IL-18, IL-1β, and caspase-3. Gene expression analysis of NFκB and TNF-α was conducted via qRT-PCR. Kidney function was evaluated by measuring serum urea and creatinine. NLRP3 protein expression was determined by western blotting, while TLR4 expression was assessed immunohistochemically. Renal tissue histology was also examined. CLP induction markedly elevated serum urea and creatinine, along with renal MDA, IL-18, IL-1β, TNF-α, NFκB, and caspase-3, and upregulated TLR4 and NLRP3 protein expression relative to the sham group, while GSH and SOD levels were notably diminished. Treatment with sacubitril/valsartan effectively ameliorated all of these biochemical and histopathological disturbances. Sacubitril/valsartan significantly attenuated CLP-induced renal injury through the suppression of inflammatory and apoptotic markers and the inhibition of the TLR4/NFκB/NLRP3/IL-1β signaling cascade.