Abstract
Carbon monoxide (CO) has shown various physiological effects including anti-inflammatory activity in several diseases, whereas the therapeutic efficacy of CO on sepsis-induced acute kidney injury (AKI) has not been reported as of yet. The purpose of the present study was to explore the effects of exogenous CO on sepsis-induced AKI and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in rats. Male rats were subjected to cecal ligation and puncture (CLP) to induce sepsis and AKI. Exogenous CO delivered from CO-releasing molecule 2 (CORM-2) was used intraperitoneally as intervention after CLP surgery. Therapeutic effects of CORM-2 on sepsis-induced AKI were assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN), kidney histology scores, apoptotic cell scores, oxidative stress, levels of cytokines TNF-α and IL-1β, and NLRP3 inflammasome expression. CORM-2 treatment protected against the sepsis-induced AKI as evidenced by reducing serum Scr/BUN levels, apoptotic cells scores, increasing survival rates, and decreasing renal histology scores. Furthermore, treatment with CORM-2 significantly reduced TNF-α and IL-1β levels and oxidative stress. Moreover, CORM-2 treatment significantly decreased NLRP3 inflammasome protein expressions. Our study provided evidence that CORM-2 treatment protected against sepsis-induced AKI and inhibited NLRP3 inflammasome activation, and suggested that CORM-2 could be a potential therapeutic candidate for treating sepsis-induced AKI.
Highlights
Sepsis is a severe clinical syndrome encountered and triggered in patients with infection, which is associated with significant mortality and morbidity
The results showed that the serum creatinine (Scr) and blood urea nitrogen (BUN) levels were significantly increased after cecal ligation and puncture (CLP) surgery (Figure 1A), which indicated that the renal function was decreased in CLP-induced septic rats
The results showed that the MDA levels were significantly higher in the CLP group than in the sham-operated control or sham plus CO-releasing molecule 2 (CORM-2) group (p < 0.01), whereas CO-releasing molecules (CORMs)-2 treatment significantly decreased the MDA levels in CLP group (p < 0.05)
Summary
Sepsis is a severe clinical syndrome encountered and triggered in patients with infection, which is associated with significant mortality and morbidity. It is well established that septic patients are at risk of developing acute kidney injury (AKI), and carry a high risk of mortality. The pathophysiology of AKI in sepsis is complex and multi-factorial and includes pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS) [1,2]. The activation of NLRP3 inflammasome promotes the maturation and release of several pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18, so it plays critical roles in the initiation of inflammation and the development of immune responses [4]. As the pro-inflammatory effect of the NLRP3 inflammasome is deleterious, the discovery of effective and specific drugs that alter NLRP3 inflammasome function has the potential to improve the symptoms of sepsis and AKI
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