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Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway.

ABSTRACT: The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN-?) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4? T cells and antigen-presenting cells (APCs) in IL-18R? knockout (KO) mice and wild-type (WT) mice after LPS injection. In the acute advanced phase, the IL-18R? KO mice showed a higher survival rate and a suppressed increase of blood urea nitrogen, increased levels of proinflammatory cytokines such as IFN-? and IL-18, the infiltration of CD4? T cells and the expression of kidney injury molecule-1 as an AKI marker. In that phase, the renal mRNA expression of the M1 macrophage phenotype and C-C chemokine receptor type 7 as the maturation marker of dendritic cells (DCs) was also significantly decreased in the IL-18R? KO mice, although there were small numbers of F4/80? cells and DCs in the kidney. Conversely, there were no significant differences in the expressions of mRNA and protein TLR4 after LPS injection between the WT and IL-18R? KO groups. Our results demonstrated that the IL-18R?-mediated signaling pathway plays critical roles in CD4? T cells and APCs and responded more quickly to IFN-? and IL-18 than TLR4 stimulation in the pathogenesis of LPS-induced AKI.

SUBMITTER: Nozaki Y

PROVIDER: S-EPMC5751375 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway.

Nozaki Yuji Y Hino Shoichi S Ri Jinhai J Sakai Kenji K Nagare Yasuaki Y Kawanishi Mai M Niki Kaoru K Funauchi Masanori M Matsumura Itaru I

International journal of molecular sciences 20171220 12

The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN-γ) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4⁺ T cells and antigen-presenting cel ...[more]

PMID: 29261164

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Project description:Background:Acute kidney injury (AKI) is often secondary to sepsis. Previous studies suggest that damaged mitochondria and the inhibition of autophagy results in AKI during sepsis, but dexmedetomidine (DEX) alleviates lipopolysaccharide (LPS)-induced AKI. However, it is uncertain whether the renoprotection of DEX is related to autophagy or the clearance of damaged mitochondria in sepsis-induced AKI. Methods:In this study, AKI was induced in rats by injecting 10 mg/kg of LPS intraperitoneally (i.p.). The rats were also pretreated with DEX (30 ?g/kg, i.p.) 30 min before the injection of LPS. The structure and function of kidneys harvested from the rats were evaluated, and the protein levels of autophagy-related proteins, oxidative stress levels, and apoptosis levels were measured. Further, atipamezole (Atip) and 3-Methyladenine (3-MA), which are inhibitors of DEX and autophagy, respectively, were administered before the injection of DEX to examine the protective mechanism of DEX. Results:Pretreatment with DEX ameliorated kidney structure and function. DEX decreased the levels of blood urea nitrogen (BUN) and creatinine (Cre), urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), and apoptosis proteins (such as cleaved caspase-9 and cleaved caspase-3). However, DEX upregulated the levels of autophagy and mitophagy proteins, such as Beclin-1, LC3 II and PINK1. These results suggest that DEX ameliorated LPS-induced AKI by reducing oxidative stress and apoptosis and enhancing autophagy. To promote autophagy, DEX inhibited the phosphorylation levels of PI3K, AKT, and mTOR. Furthermore, the administration of Atip and 3-MA inhibitors blocked the renoprotection effects of DEX. Conclusions:Here, we demonstrate a novel mechanism in which DEX protects against LPS-induced AKI. DEX enhances autophagy, which results in the removal of damaged mitochondria and reduces oxidative stress and apoptosis in LPS-induced AKI through the ?2-AR and inhibition of the PI3K/AKT/mTOR pathway.

Project description:BACKGROUND:Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS:We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. RESULTS:The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. CONCLUSIONS:High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).

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Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway.

Publications

Lipopolysaccharide-Induced Acute Kidney Injury Is Dependent on an IL-18 Receptor Signaling Pathway.

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