Dexmedetomidine protects against lipopolysaccharide-induced sepsis-associated acute kidney injury via an α7 nAChR-dependent pathway

Kang, Kai; Gao, Yang; Wang, Si-Cong; Liu, Haitao; Kong, Wei; Zhang, Xing; Huang, Rui; Qi, Zhi-Dong; Zheng, Jie; Qu, Jingdong; Liu, Ruijin; Liu, Yansong; Wang, Hongliang; Yu, Kaijiang

doi:10.1016/j.biopha.2018.06.059

Cited by 44 publications

(36 citation statements)

References 31 publications

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“…AKI was induced by injecting intraperitoneally (IP) LPS (Escherichia coli 0111: B4; Sigma-Aldrich) as described before. 6 Briefly, LPS was dissolved in a concentration of 10 mg/mL using normal saline. 6 Thirty rats were randomly assigned to five groups (n = 6 per group): the CON group (…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Dexmedetomidine alleviates lipopolysaccharide‐induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway

Yao

Feng

et al. 2019

J of Cellular Biochemistry

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Dexmedetomidine (DEX) prevents kidney damage caused by sepsis, but the mechanism of this effect remains unclear. In this study, the protective molecular mechanism of DEX in lipopolysaccharide (LPS)‐induced acute kidney injury was investigated and its potential pharmacological targets from the perspective of inhibiting oxidative stress damage and the nucleotide‐binding domain‐like receptor protein 3 (NLRP3) inflammasome activation. Intraperitoneal injection of DEX (30 μg/kg) significantly improved LPS (10 mg/kg) induced renal pathological damage and renal dysfunction. DEX also ameliorated oxidative stress damage by reducing the contents of reactive oxygen species, malondialdehyde and hydrogen peroxide, and increasing the level of glutathione, as well as the activity of superoxide dismutase and catalase. In addition, DEX prevented nuclear factor‐kappa B (NF‐κB) activation and I‐kappa B (IκB) phosphorylation, as well as the expressions of NLRP3 inflammasome‐associated protein and downstream IL‐18 and IL‐1β. The messengerRNA (mRNA) and protein expressions of toll‐like receptor 4 (TLR4), NADPH oxidase‐4 (NOX4), NF‐κB, and NLRP3 were also significantly reduced by DEX. Their expressions were further evaluated by immunohistochemistry, yielding results were consistent with the results of mRNA and protein detection. Interestingly, the protective effects of DEX were reversed by atipamezole‐an alpha 2 adrenal receptor (α2AR) inhibitor, whereas idazoxan‐an imidazoline receptor (IR) inhibitor failed to reverse this change. In conclusion, DEX attenuated LPS‐induced AKI by inhibiting oxidative stress damage and NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway, mainly acting on the α2AR rather than IR.

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Section: Animals and Treatmentsmentioning

confidence: 99%

Dexmedetomidine alleviates lipopolysaccharide‐induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway

Yao

Feng

et al. 2019

J of Cellular Biochemistry

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“…The kidney is one of the most vulnerable organs during sepsis, and acute kidney injury (AKI) occurs in 40-50% of septic patients with a mortality rate of up to 60% (Plotnikov et al, 2019). The underlying pathogenesis of sepsis acute kidney injury (SAKI) is not well understood but includes oxidative stress (Chen et al, 2019), inflammation (Feng et al, 2019), and apoptosis (Kang et al, 2018). Recently, it was reported that autophagy played a key role in SAKI, and the inhibition of autophagy resulted in the development of AKI during sepsis (Ho et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

et al. 2020

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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 mg/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

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“…Dexmedetomidine (DEX) possesses several properties that are potentially beneficial for treating AKI. It is a potent and highly selective α 2 adrenergic agonist with analgesic, sedative, and antisympatholytic characteristics [7,8]. The distal and proximal tubules of the kidney, as well as the peritubular vasculature, are rich in α 2 -adrenoceptors [7,8].…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Protects against Ischemia and Reperfusion-Induced Kidney Injury in Rats

Bao

Dai

2020

Mediators of Inflammation

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Acute kidney injury (AKI), a clinical syndrome, is a sudden onset of kidney failure that severely affects the kidney tubules. One potential treatment is dexmedetomidine (DEX), a highly selective α2-adrenoreceptor agonist that is used as an anesthetic adjuvant. It also has anti-inflammatory, neuroprotective, and sympatholytic qualities. The aim of this study was to establish whether DEX also offers protection against ischemia and reperfusion- (I/R-) induced AKI in rats. An intraperitoneal injection of DEX (25 μg/kg) was administered 30 min prior to the induction of I/R. The results indicate that in the I/R rats, DEX played a protective role by reducing the damage to the tubules and maintaining renal function. Furthermore, in response to I/R, the DEX treatment reduced the mRNA expression of TNF-α, IL-1β, IL-6, and MCP-1 in the kidney tissues and the serum levels of TNF-α, IL-1β, IL-6, and MCP-1. DEX also reduced the levels of oxidative stress and apoptosis in the tubular cells. These results indicate that in response to I/R kidney injury, DEX plays a protective role by inhibiting inflammation and tubular cell apoptosis, reducing the production of reactive oxygen species, and promoting renal function.

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Dexmedetomidine protects against lipopolysaccharide-induced sepsis-associated acute kidney injury via an α7 nAChR-dependent pathway

Cited by 44 publications

References 31 publications

Dexmedetomidine alleviates lipopolysaccharide‐induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway

Dexmedetomidine alleviates lipopolysaccharide‐induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF‐κB pathway

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Dexmedetomidine Protects against Ischemia and Reperfusion-Induced Kidney Injury in Rats

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