Aprocitentan mitigates ischemia reperfusion induced kidney injury in rats by attenuating inflammation and pyroptosis through suppressing NF-κB/NLRP3/caspase-1 signaling pathway

Abstract

Introduction and aim. Renal ischemia-reperfusion (I/R) injury is a primary cause of acute kidney injury (AKI). The NF-κB/NLRP3/caspase-1 signaling system is crucial for I/R-induced kidney damage, which leads to inflammation, pyroptosis, and tissue damage. Aprocitentan has anti-inflammatory and vasoprotective properties, suggesting its potential nephroprotective advantages. The aim of this investigation was to evaluate the protective advantages of aprocitentan against renal I/R injury in rat models. This was achieved by evaluating the impact of aprocitentan on inflammation, pyroptosis, and kidney function by altering the NF-κB/NLRP3/Caspase-1 pathway. Material and methods. Using twenty-four adult male Sprague-Dawley rats, four separate groups were formed: sham group, I/R control group, dimethyl sulfoxide group (DMSO) and aprocitentan group (10 mg/kg). Renal ischemia/reperfusion was induced by a period of forty minutes of bilateral ischemia, which was followed by two hours of reperfusion. To evaluate the renoprotective effect of aprocitentan urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), phosphorylated nuclear factor kappa B p65 (NF-κB p65), NOD-like receptor protein 3 (NLRP3), and cysteine-aspartic protease-1 (caspase-1), were measured, along with histopathological examination. Results. Compared to the sham group, the I/R control group had significantly increased concentrations of urea, creatinine, NGAL, NF-κB p65, NLRP3, as well as caspase-1. These signs decreased in the aprocitentan group, leading to enhanced renal function, reduction of inflammation, and inhibition of pyroptosis. Histology showed a decrease in tubular inflammation and necrosis in the aprocitentan group. Conclusion. Aprocitentan decreases inflammation and inhibits pyroptosis by suppressing the NF-κB/NLRP3/Caspase-1 pathway. These results illustrate its promising potential to prevent ischemic renal diseases, including acute kidney injury.