Acute kidney injury (AKI), which is associated with high mortality rates, involves renal inflammation related to the activation of innate immunity. The inflammatory response in AKI involves the inflammasome, which integrates danger signals into caspase-1-activating platforms, leading to the processing and secretion of the proinflammatory cytokines interleukin (IL)-1b and IL-18. The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome plays a role in the development of many diseases, including AKI. However, the mechanisms by which the NLRP3 inflammasome translates different danger signals into the expression of proinflammatory cytokines remain unclear. Here, we investigated the role of the NLRP3 inflammasome in renal injury in a cecal ligation and puncture (CLP) model of sepsis-induced AKI. CLP decreased blood pressure and increased serum creatinine levels and neutrophil infiltration into the kidney in parallel with the upregulation of NLRP3, the adaptor protein apoptosisassociated speck-like protein, and caspase-1 expression and activity in kidney tissues, and increases in the serum and kidney levels of IL-1b and IL-18. Genetic deletion of NLRP3 reversed the CLP-induced reduction in blood pressure and increases in serum creatinine level and neutrophil infiltration, and attenuated the CLP-induced upregulation of apoptosis-associated speck-like protein, caspase-1 expression and activity, and the secretion of IL-1b and IL-18, similarly to the effects of caspase-1 inhibition. Taken together, our results indicate that activation of the NLRP3 inflammasome contributes to the development of hypotension and the inflammatory response of AKI, suggesting its possible role as a therapeutic target for the treatment of kidney diseases.
This study investigated the effects of heme oxygenase 1 (HO-1) on thrombomodulin (TM) and endothelial protein C receptor (EPCR) expression in sepsis-induced kidney injury. The role of HO-1 was evaluated in a cecal ligation and puncture (CLP)-induced model. Wistar rats were randomly assigned into four groups: sham, CLP, CLP + hemin (an HO-1 inducer), CLP + ZnPP (zinc protoporphyrin IX, an HO-1 inhibitor), and CLP + bilirubin. Compared with the sham group, the CLP group exhibited significantly elevated plasma levels of cystatin C, creatinine, urea nitrogen (blood urea nitrogen), tumor necrosis factor α, interleukin 1β, TM, and EPCR; lower plasma level of activated protein C, shorter prothrombin time and activated partial thromboplastin time; significantly increased microthrombus formation; and lower TM and EPCR mRNA and protein expression in the kidney. The administration of hemin lowered the plasma levels of cystatin C, creatinine, blood urea nitrogen, tumor necrosis factor α, interleukin 1β, TM, and EPCR; elevated plasma level of activated protein C; prolonged prothrombin time and activated partial thromboplastin time; attenuated microthrombus formation; and upregulated the expression of TM and EPCR and mRNA levels of TM and EPCR in the kidney in the CLP + hemin group. In contrast, ZnPP had the opposite effects. The results indicated that the enhanced induction of HO-1 increased the expression of TM and EPCR in the kidney and exerted an anticoagulant effect, thereby attenuating kidney injury in septic rats.
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