Abstract
Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.
Highlights
Sepsis is a life-threatening organ dysfunction caused by systemic infection [1], and accounted for 11 million deaths worldwide in 2017 [2]
We investigated whether lipoxin A4 (LXA4) can attenuate cecal ligation and puncture (CLP)induced Acute kidney injury (AKI) by inhibiting the NF-kB network in a peroxisome proliferator activated receptor (PPAR)-gdependent manner
Consistent with septic renal injury, we observed that renal tubular epithelial cell senescence increased significantly in the CLP group compared to the sham group, and the percentage of b-gal-positive area increased over time (Figures 1G, H), which prompted us to consider senescence as an important cause of renal injury induced by sepsis
Summary
Sepsis is a life-threatening organ dysfunction caused by systemic infection [1], and accounted for 11 million deaths worldwide in 2017 [2]. More than 50% of patients with sepsis develop acute kidney injury (AKI), which is considered a critical pathophysiology of sepsis [3]. Targeting septic AKI is of great significance in reducing the mortality associated with sepsis. Increasing evidence indicates that the pathogenesis of AKI with sepsis is complex and multifactorial, involving the interplay among oxidative stress, inflammation and cellular injury [4]. Premature cell senescence has emerged as an important feature of AKI [5]. Acute DNA damage response has been found to induce inflammation and senescence, and is called stress-induced premature senescence (SIPS) [6]. Our earlier study showed that sepsis causes renal tubular cell senescence [8]. The role of renal tubular cell senescence in septic AKI is largely unknown
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