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Purpose: We aim to detect the effects of sivelestat on renal ischemia-reperfusion associated with AKI and also explore the underlying mechanism., Materials and Methods: Mice, aged between 8 and 12 weeks, were randomly allocated among four distinct groups, respectively normal saline sham group(C), normal saline surgery group(I), sivelestat (50 mg/kg) sham group(S), sivelestat (50 mg/kg) surgery group(SI) (n=6, each group). In the surgical groups, the renal pedicles of mice were clamped with non-traumatic micro-aneurysm clamps, resulting in ischemia of the kidneys for 45 minutes. This was followed by a period of reperfusion lasting 24 hours. Sham group mice underwent the identical surgery produced without clamping renal pedicles. Mice blood was obtained from eyeballs, and Serum creatinine and blood urea nitrogen levels were measured. After a 24-hour period of reperfusion, the mice were euthanized, and their kidneys were gathered for various analyses, including Western Blot (WB) analysis, RT-PCR, immunofluorescence (IF), hematoxylin and eosin (H&E) staining, and Tunel assay., Results: Pretreatments with sivelestat decreased renal Neutrophil elastase (NE), serum creatinine, and blood urea nitrogen levels after renal ischemia-reperfusion. Sivelestat also reduced histological damage and cell apoptosis in kidneys following ischemia-reperfusion injury (IRI). In addition, the sivelestat administration diminished the levels of mRNA expression of interleukin 6 (IL-6), Macrophage inflammatory protein-2 (MIP-2), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-α in the kidneys during IRI. The kidney tissues of the SI group had significantly mitigated TLR4, Myd88, and NF-κB p-p65 protein expression levels compared to the I group (all P<0.05)., Conclusion: We demonstrated a previously unidentified mechanism that sivelestat effectively attenuates AKI-induced renal dysfunction, possibly through suppressing the TLR4/Myd88/ NF-κB pathway., Competing Interests: The author(s) report no conflicts of interest in this work., (© 2024 Wang et al.)

Inflammatory cells contribute to the pathogenesis of renal ischemia-reperfusion injury (IRI). However, the signaling mechanisms underlying the infiltration of inflammatory cells into the kidney are not well understood. In this study, we examined the effects of phosphoinositide 3 kinase γ (PI3Kγ) on inflammatory cells infiltration into the kidney in response to ischemia-reperfusion injury. Compared with wild-type mice, PI3Kγ knockout mice displayed less IRI in the kidney with fewer tubular apoptotic cell. Furthermore, PI3Kγ deficiency decreased the number of infiltrated neutrophils, macrophages, and T cells in the kidney, which was accompanied by a decrease in the expression of pro-inflammatory cytokines in the kidney. Moreover, wild-type mice treated with AS-605240, a selective PI3Kγ inhibitor, displayed less tubular damage, accumulated fewer inflammatory cells, and expressed less proinflammatory molecules in the kidney following IRI. These results demonstrate that PI3Kγ has a critical role in the pathogenesis of kidney damage in IRI, indicating that PI3Kγ inhibition may serve as a potential therapeutic strategy for the prevention of ischemia-reperfusion-induced kidney injury.

Background: Acute kidney injury (AKI) is associated with a substantially increased risk of mortality for many hospitalized patients. It has been suggested that early initiation of renal replacement treatment has a favorable outcome in critically ill patients complicated with AKI. However, results of studies evaluating the effect of early initiation strategy of renal replacement treatment on AKI have been controversial and contradictory. The aim of this meta-analysis is to examine the effect of early initiation of renal replacement treatment on patients with AKI., Methods: The authors searched relevant studies in PubMed, EMBASE, and the Cochrane Library through August 2016. We searched for all eligible randomized controlled trials with regard to the role of early initiation of renal replacement treatment in mortality among patients with AKI. We extracted the following information from each study: mortality, length of stay in intensive care unit (ICU), and length of stay in hospital. Random and fixed effect models were used for pooling data., Results: Twelve trials including 1756 patients were included. The results of this meta-analysis showed that there was no significant difference between the mortality of early and delayed strategy for the initiation of renal replacement treatment using the random effect model (odds ratio = 0.78; 95% confidence interval [CI], 0.52-1.19; P = 0.25), with wild heterogeneity (chi = 33.50; I = 67%). Analyses from subgroup sepsis and postsurgery came to similar results. In addition, compared with delayed initiation strategy, early initiation showed no significant advantage in length of stay in ICU (mean difference = -0.80; 95% CI, -2.59 to 0.99; P = 0.56) and length of stay in hospital (mean difference = -7.69; 95% CI, -16.14 to 0.76; P = 0.07)., Conclusion: According to the results from present meta-analysis, early initiation of renal replacement treatment showed no survival benefits in patients with AKI. To achieve optimal timing of renal replacement treatment, further large multicenter randomized trials, with widely accepted and standardized definition of early initiation, are still needed., Competing Interests: The authors have no conflicts of interest to disclose.