College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
Nitric Oxide. 2019 Apr 1;85:1-9. doi: 10.1016/j.niox.2019.01.009. Epub 2019 Jan 17.
Increasing evidence has demonstrated that dexmedetomidine (DEX) possesses multiple pharmacological actions. Herein, we explored the protective effect and potential molecular mechanism of DEX on lipopolysaccharide (LPS)-induced early acute kidney injury (AKI) from the perspective of antioxidant stress. We found that DEX (30 μg/kg, i.p.) ameliorated the renal dysfunction and histopathological damage (tubular necrosis, vacuolar degeneration, infiltration of inflammatory cells and cast formation) induced by LPS (10 mg/kg). DEX also attenuated renal oxidative stress remarkably in LPS-induced early AKI, as evidenced by reduction in production of reactive nitrogen species, decreasing malondialdehyde levels, as well as increasing superoxide dismutase activity and glutathione content. DEX prevented activator protein-1 translocation, inhibited phosphorylation of I-kappa B (IκB) and activation of nuclear factor kappa B (NF-κB) in LPS-induced early AKI, as assessed by real-time quantitative polymerase chain reaction and protein levels of c-Jun, c-Fos, IκB and NF-κB. Notably, DEX pretreatment had the same effect as intraperitoneal injection of an inhibitor of inducible nitric oxide synthase inhibitor (1400W; 15 mg/kg), and inhibited the activity of renal inducible nitric oxide synthase (iNOS) and decreased the expression of iNOS mRNA and NO production. However, the protective effect of DEX on LPS-induced early AKI was reversed by the alpha 2 adrenal receptor (α-AR) inhibitor atipamezole, whereas the imidazoline receptor inhibitor idazoxan did not. Taken together, DEX protects against LPS-induced early AKI in rats by inhibiting the iNOS/NO signaling pathway, mainly by acting on α-ARs instead of IRs.
越来越多的证据表明，右美托咪定（DEX）具有多种药理学作用。在此，我们从抗氧化应激的角度探讨了 DEX 对脂多糖（LPS）诱导的早期急性肾损伤（AKI）的保护作用及其潜在的分子机制。我们发现，DEX（30μg/kg，腹腔注射）可改善 LPS（10mg/kg）诱导的早期 AKI 引起的肾功能障碍和组织病理学损伤（肾小管坏死、空泡变性、炎症细胞浸润和铸型形成）。DEX 还显著减轻 LPS 诱导的早期 AKI 中的肾氧化应激，表现为活性氮物种生成减少，丙二醛水平降低，超氧化物歧化酶活性和谷胱甘肽含量增加。DEX 可防止 LPS 诱导的早期 AKI 中激活蛋白-1 易位，抑制 I-κB（IκB）磷酸化和核因子 kappa B（NF-κB）的激活，通过实时定量聚合酶链反应和 c-Jun、c-Fos、IκB 和 NF-κB 的蛋白水平进行评估。值得注意的是，DEX 预处理与腹腔注射诱导型一氧化氮合酶抑制剂（1400W；15mg/kg）具有相同的效果，并抑制肾诱导型一氧化氮合酶（iNOS）的活性，降低 iNOS mRNA 的表达和 NO 的产生。然而，DEX 对 LPS 诱导的早期 AKI 的保护作用被α 2 肾上腺受体（α-AR）抑制剂阿替美唑逆转，而咪唑啉受体抑制剂伊达唑则没有。综上所述，DEX 通过抑制 iNOS/NO 信号通路来保护 LPS 诱导的早期 AKI，主要通过作用于 α-AR 而不是 IR 来发挥作用。
