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

Abstract

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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“…extract decreased the inflammatory response and OS via activation of the Akt signaling pathway in an LPS-shock mouse model ( 60 ). Zhao et al ( 61 ) reported that dexmedetomidine protected against LPS-mediated AKI in rats via inhibiting the activation of the Akt signaling pathway. Additionally, another study demonstrated that water extracts from the roots of E. purpurea containing a polysaccharide with anti-inflamma-tory properties activated the Akt signaling pathway in human acute monocytic leukemia (THP-1) cells ( 62 ).…”

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“…LC3, P62, and Beclin-1 are autophagyrelated proteins. Beclin-1 interacts with PI3K to trigger autophagy and then participates in the subsequent steps of the fusion of autophagosomes and lysosomes (Zhao et al, 2020). LC3 combines with the autophagosome membrane to form a complete autophagosome, and then fuses and degrades with lysosomes (Currarino et al, 1976).…”

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

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