Inhibiting pannexin-1 alleviates sepsis-induced acute kidney injury via decreasing NLRP3 inflammasome activation and cell apoptosis

Sepsis-induced acute kidney injury (SI-AKI) is the fifth most common cause of hospital-acquired acute kidney injury. Pannexin1 (Panx1) triggers inflammation and apoptosis which act as crucial factors in the pathogenesis of SI-AKI. We aimed to investigate the expression of Panx1 and its role on the inflammation and apoptosis in SI-AKI. SI-AKI model was established by lipopolysaccharide (LPS) injection in mice and LPS-treated HK-2 cells in vitro. Panx1 was inhibited by pretreating with carbenoxolone (CBX) or small interfering RNA in vivo and vitro, respectively. The expression of Panx1 was determined by qPCR, western blot and immunohistochemistry (IHC). Kidney damage was evaluated by kidney function, histopathological examination and AKI biomarkers. Inflammatory cytokines were detected by qPCR and ELISA. Apoptosis was detected by TUNEL staining and the expression of apoptosis-related proteins. The activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome was measured by western blot. Panx1 increased in LPS-induced SI-AKI mice and HK-2 cells, as well as in SI-AKI patients. CBX alleviated the renal function and pathological damage, as well as decreased the mRNA of kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Inhibiting Panx1 decreased the production of IL-1β, IL-6 and TNF-α, as well as tubular cell apoptosis in SI-AKI. Inhibiting Panx1 suppressed inflammatory cytokines and apoptosis via inhibiting NLRP3 inflammasome activation and regulating apoptotic protein Bax and Bcl2 expression, respectively. These observations suggest that pharmacological inhibition of Panx1 might be a potential approach in the clinical therapy of SI-AKI.