Abstract
Bacterial endotoxin has been known to induce excessive inflammatory responses and acute kidney injury. In the present study, we used a mouse model of endotoxemia to investigate the role of Sirt1 in inflammatory kidney injury. We examined molecular and cellular responses in inducible Sirt1 knockout (Sirt1−/−) mice and wild type littermates (Sirt1+/+) in lipopolysaccharide (LPS)-induced kidney injury. Our studies demonstrated that Sirt1 deletion caused aggravated kidney injury, which was associated with increased inflammatory responses including elevated pro-inflammatory cytokine production, and increased ICAM-1 and VCAM-1 expression. Inflammatory signaling such as STAT3/ERK phosphorylation and NF-κB activation was markedly elevated in kidney tissues of Sirt1 knockout mice after LPS challenge. The results indicate that Sirt1 is protective against LPS-induced acute kidney injury by suppressing kidney inflammation and down-regulating inflammatory signaling.
Highlights
Sepsis arises mostly from bacterial infection which causes multiple organ failure due to excessive systemic inflammation [1,2]
Sirt1 deletion leads to aggravated renal dysfunction after LPS challenge
blood urea nitrogen (BUN) and Kidney injury molecule-1 (KIM-1) levels were increased after LPS challenge, and significantly higher in Sirt1 knockout mice than the wild type littermates (Figure 1 A, B), indicating exacerbated renal dysfunction in Sirt1 knockout mice
Summary
Sepsis arises mostly from bacterial infection which causes multiple organ failure due to excessive systemic inflammation [1,2]. Kidney functions as a natural filter of blood and serves as the first line of defense in our body [3,4]. It becomes a direct target of inflammatory injury [5]. Sepsis-induced acute kidney injury (AKI) is very common in the elderly and associated with high mortality [6,7,8]. There has been no effective treatment for this devastating disease [9,10]. Lipopolysaccharide (LPS) challenge is one of the most accepted animal models to explore the underlying mechanisms and potential treatment in sepsis-induced kidney injury [11]
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