Dexmedetomidine protects against lipopolysaccharide-induced early acute kidney injury by inhibiting the iNOS/NO signaling pathway in rats

Chen, Yongping; Li, Luan; Wang, Chaoran; Song, Manyu; Zhao, Yuan; Yao, Yujie; Yang, Haotian; Ma, Biao; Fan, Honggang

doi:10.1016/j.niox.2019.01.009

Cited by 35 publications

(37 citation statements)

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“…BUN and Cre are important indicators of the severity of renal impairment. Furthermore, NGAL and KIM-1 have been identified as specific biomarkers of kidney injury (Han et al, 2002;Bolignano et al, 2008), and their increased expression is associated with early renal tubular injury in AKI (Chen et al, 2019). The levels of BUN ( Figure 1Aa), Cre (Figure 1Ab), KIM-1 ( Figure 1Ac), and NGAL ( Figure 1Ad) were significantly increased after LPS injection, and DEX pretreatment significantly decreased the levels of these markers, which indicated that DEX alleviates LPS-induced kidney injury.…”

Section: Effects Of Dex On Renal Function and Structural Changesmentioning

confidence: 99%

“…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 (DEX) is a highly selective alpha-2 adrenergic receptor (a 2 -AR) agonist (Kawazoe et al, 2017). Our previous studies have shown that DEX exhibits anti-inflammatory and anti-oxidative effects in LPS-induced AKI (Chen et al, 2019;Feng et al, 2019;Yao et al, 2019). It has also demonstrated that DEX has anti-inflammatory and anti-apoptotic effects in LPS-induced AKI (Kang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Effects Of Dex On Renal Function and Structural Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…using Pi3K-knockout mice, it was previously revealed that a conventional dose of cP was more lethal in these knockout mice, indicating the importance of the Pi3K/aKT pathway in protecting the kidneys (21). dexmedetomidine (dex), a highly selective α 2 adrenoreceptor (α 2 AR) agonist, has been reported to be beneficial for the prevention of numerous types of kidney diseases, including acute stress-induced kidney injury (22), ischemia-reperfusion and sepsis-induced kidney injuries (23)(24)(25). it has also been demonstrated that dex protects the kidney against cP-induced AKI by regulating apoptosis and the inflammatory response (26).…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine alleviates cisplatin‑induced acute kidney injury by attenuating endoplasmic reticulum stress‑induced apoptosis via the α2AR/PI3K/AKT pathway

Chai

Zhu

et al. 2020

Mol Med Report

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cisplatin (cP) is an effective antineoplastic agent; however, cP-induced acute kidney injury (aKi) seriously affects the prognosis of patients with cancer. endoplasmic reticulum (er) stress (erS)-induced apoptosis serves a pivotal role in the pathogenesis of cP-induced aKi. dexmedetomidine (dex), a potent α 2 adrenergic agonist, has been reported to exert protective effects against aKi. However, the protective effects of dex against cP-induced aKi and the potential molecular mechanisms remain unknown. in the present study, male Sprague-dawley rats were divided into four groups (n=10/group), as follows: control group; cP group, rats received an intraperitoneal (i.p.) injection of 5 mg/kg cP; dex + cP group, rats received an i.p. injection of 25 µg/kg dex immediately after cP treatment; and dex + cP + atipamezole (atip) group, rats received an i.p. injection of 250 µg/kg atip, an α 2 adrenoreceptor (α 2 ar) antagonist, and then received the same treatment as the dex + cP group. rats were anesthetized and sacrificed 96 h after CP injection. Subsequently, serum blood urea nitrogen (Bun) and serum creatinine (Scr) were analyzed, and kidney samples were collected for analyses. Pathological changes were examined using hematoxylin and eosin staining, and protein expression levels were assessed using western blotting and immunohistochemical staining. in addition, apoptosis was examined using a terminal deoxynucleotidyl transferase duTP nick-end labeling assay. The present results suggested that dex protected against cP-induced aKi by attenuating histological changes in the kidney, serum Bun and Scr production. Furthermore, the expression levels of 78-kda glucose-regulated protein, c/eBP homologous protein and caspase-12, and the apoptotic rate in the kidney were decreased following dex treatment. in addition, the expression levels of phosphorylated (p)-Pi3K and p-aKT in the dex + cP group were significantly increased. Conversely, the renoprotective effects of dex were attenuated following the addition of atip. in conclusion, dex may alleviate cP-induced aKi by attenuating erS-induced apoptosis, at least in part, via the α 2 ar/Pi3K/aKT signaling pathway.

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“…To date, the mechanisms of such action are at the initial stage of their study. It is known about the reduction of lipid peroxidation products, the production of peroxynitrile radicals [51], the stimulation of the activity of endogenous glutathione and superoxide dismutase [52]. A significant role in this case is given to stabilization of the inner mitochondrial membranes [53,54].…”

Section: The Analysis Of Trends and Directions Of Research Of α2-am-amentioning

confidence: 99%

Tendencies and perspectives of central alpha2-adrenomimetic application in medicobiological research

et al. 2019

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The pharmacodynamic effects of the administration of 2-adrenergic agonists both in a monovariant and in combination with drugs of other pharmacological groups are considered. Based on analysis of safety nonclinical studies the characteristics of main physiological effects of 2-adrenergic receptors as well as physiological effects of 2-agonists on various organs and systems are presented. For the determination of tendencies and directions in research of central 2-AM (dexmedetomidine) the analysis of bibliographical data, accumulated and extracted from Medline database with 5 year time-filter (VOSviewer, 1.6.11 version) has been carried out. For the further research of central 2-adrenomimetics and their application in clinical practice the following perspective directions have been determined: the study of effects and mechanisms of cytoprotectant and antioxidant action, the study of the use of drugs in a monovariant and in combinations for the development of analgesic drugs, anesthesia and development of combined formulations with a delayed release of antagonists designed to mitigate side effects.

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Dexmedetomidine protects against lipopolysaccharide-induced early acute kidney injury by inhibiting the iNOS/NO signaling pathway in rats

Cited by 35 publications

References 50 publications

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

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

Dexmedetomidine alleviates cisplatin‑induced acute kidney injury by attenuating endoplasmic reticulum stress‑induced apoptosis via the α2AR/PI3K/AKT pathway

Tendencies and perspectives of central alpha2-adrenomimetic application in medicobiological research

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