Dexmedetomidine Enhances Autophagy via α2-AR/AMPK/mTOR Pathway to Inhibit the Activation of NLRP3 Inflammasome and Subsequently Alleviates Lipopolysaccharide-Induced Acute Kidney Injury

Abstract

Background: Acute kidney injury (AKI) is a severe complication of sepsis; however, no effective drugs have been found. Activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome is a major pathogenic mechanism of AKI induced by lipopolysaccharide (LPS). Autophagy, a process of intracellular degradation related to renal homeostasis, effectively restricts inflammatory responses. Herein, we explored the potential protective mechanisms of dexmedetomidine (DEX), which has confirmed antiinflammatory effects, on LPS-induced AKI. Methods: AKI was induced in rats by injecting 10 mg/kg of LPS intraperitoneally (i.p.). Wistar rats received intraperitoneal injections of DEX (30 µg/kg) 30 min before an intraperitoneal injection of LPS. Atipamezole (ATI) (250 µg/kg) and 3-methyladenine (3-MA) (15 mg/kg) were intraperitoneally injected 30 min before the DEX injection. Results: DEX significantly attenuated renal injury. Furthermore, DEX decreased activation of the NLRP3 inflammasome and expression of interleukins 1b and 18. In addition, autophagy-related protein and gene analysis indicated that DEX could significantly enhance autophagy. Finally, we verified the pharmacological effects of DEX on the 5′adenosine monophosphate-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway. Atip and 3-MA significantly reversed the protective effects of DEX. Conclusions: Our results suggest that the protective effects of DEX were mediated by enhanced autophagy via the a 2-adrenoreceptor/AMPK/mTOR pathway, which decreased

Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway

“…Meanwhile, the LC3II ratios and Beclin1 levels in the livers of the CLP mice treated with DEX were higher than those in livers of the CLP mice, whereas the level of p62 was lower, suggesting increased and fluent autophagic flux in the CLP + DEX group. These findings are supported by recent reports of increased autophagy in the heart and kidney of CLP-induced animals treated with DEX ( Yu et al, 2019 ; Yang et al, 2020 ; Zhao et al, 2020 ).…”

“…In response to energy depletion or stress conditions, phosphorylated AMPK ( p -AMPK) increases SIRT1 expression, thereby triggering autophagy to regulate energy homeostasis and metabolic stress ( Sun et al, 2018 ). Recently, DEX has been confirmed to exert its protective effects by activating AMPK and suppressing inflammatory responses ( Wang et al, 2018 ; Yang et al, 2020 ). A previous study demonstrated that hepatocyte AMPKα1 is a key regulator of liver metabolic and innate immune function ( Kikuchi et al, 2020 ).…”

“…Dexmedetomidine was reported as beneficial for septic challenge via inducing autophagy. Previous studies demonstrated that DEX, by regulating the autophagy level, exerts an organ-protective effect against sepsis, including septic acute kidney injury Yang et al (2020) , Zhao et al (2020) and septic myocardial dysfunction ( Yu et al, 2019 ). However, whether the protective effect of DEX on sepsis-induced liver injury is related to autophagy remains unclear.…”

Response to Pegylated Interferon in a COVID-19 Positive Male with Metastatic Jejunal Neuroendocrine Tumor Treated with Everolimus

“…mTOR stimulates the NLRP3 inflammasome by increased mitochondrial reactive oxygen species formation and inhibiting autophagy 28 . As predicted, mTOR inhibitors inhibit NLRP3 inflammasome induced hyper-inflammation in vitro andin vivo 29,30 .…”

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“…Dexmedetomidine was reported as beneficial for septic challenge via inducing autophagy. Previous studies demonstrated that DEX, by regulating the autophagy level, exerts an organ-protective effect against sepsis, including septic acute kidney injury Yang et al (2020), Zhao et al (2020) and septic myocardial dysfunction (Yu et al, 2019). However, whether the protective effect of DEX on sepsis-induced liver injury is related to autophagy remains unclear.…”