Dexmedetomidine ameliorates lipopolysaccharide-induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK-3β/Nrf2 signaling pathway.

Acute kidney injury (AKI) is a frequent and serious complication of sepsis; however, there are currently no effective therapies. Inflammation and oxidative stress are the major mechanisms implicated in lipopolysaccharide (LPS)-induced AKI. Dexmedetomidine (DEX) has been reported to have remarkable anti-inflammatory and antioxidant effects. Here, we examined the renoprotective effects of DEX and potential underlying mechanisms in rats with LPS-induced AKI. We analyzed renal function and structure; serum inflammatory cytokine; renal oxidant and antioxidant levels; and renal expression of glycogen synthase kinase-3β (GSK-3β)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related proteins in rats 4 hr after administration of LPS. Pretreatment with DEX improved renal function and significantly reduced the levels of inflammatory cytokines and oxidative stress markers. Treatment with DEX and the GSK-3β inhibitor SB216367 promoted phosphorylation of GSK-3β, induced Nrf2 nuclear translocation, and increased transcription of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, primarily in renal tubules. Alpha-2-adrenergic receptor (α2-AR) antagonist atipamezole and imidazoline I 2 receptor (I 2 R) antagonist idazoxan reversed the effects of DEX. These results suggest that the renoprotective effects of DEX are mediated via α2-AR and I 2 R-dependent pathways that reduce inflammation and oxidative stress through GSK-3β/Nrf2 signaling.

Feng X ，Guan W ，Zhao Y ，Wang C ，Song M ，Yao Y ，Yang T ，Fan H ... -  《-》

Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor.

Dexmedetomidine (DEX) protects against liver damage caused by sepsis. The purpose of this study was to confirm the regulatory effects of DEX on glycogen synthase kinase 3 beta (GSK-3β) via the α2 adrenergic receptor (α2AR) and evaluate the role of GSK-3β in lipopolysaccharide (LPS)-induced liver injury. Sprague-Dawley (SD) rats were administered an intraperitoneal injection of DEX (30 μg/kg) 30 min before an intraperitoneal injection of LPS (10 mg/kg). HE staining and serum biochemical test results indicated that DEX significantly improved liver histopathological damage and liver function indices. Furthermore, DEX increased super oxide dismutase (SOD) activity and L-glutathione (GSH) levels, and inhibited malondialdehyde (MDA) production. Western blot (WB) analysis demonstrated that treatment with the GSK-3β inhibitor SB216763 increased antioxidant-related protein mitogen-activated protein kinase phosphatase 1 (MKP-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. In addition, anti-apoptosis-related proteins were up-regulated and pro-apoptosis-related proteins were down-regulated by SB21676 administration. WB analysis also showed that DEX increased anti-apoptosis-related protein levels and decreased pro-apoptotic protein levels in LPS-induced liver injury. Nrf2, p53, and activated caspase-3 levels were further evaluated using immunohistochemistry (IHC), producing results consistent with WB results. The α2AR antagonist atipamezole (AT) significantly reversed the protective effects of DEX, as shown by WB analysis. Our data suggested that α2AR plays an important role in reversing the effects of liver oxidative stress and apoptosis via DEX, and that DEX exerts antioxidant and anti-apoptosis effects through regulation of the GSK-3β/MKP-1/Nrf2 pathway.

Sha J ，Zhang H ，Zhao Y ，Feng X ，Hu X ，Wang C ，Song M ，Fan H ... -  《-》

Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3β/STAT3-NF-κB signaling pathway in rats.

Acute lung injury (ALI) is a serious complication of sepsis and an important cause of death in intensive care. Studies have shown that DEX can inhibit inflammation. However, the anti-inflammatory effect and protective mechanism of DEX in lipopolysaccharide (LPS) induced ALI are still unclear. ALI model was established by intraperitoneal injection of LPS (10 mg/kg) in Sprague-Dawley (SD) male rats. Firstly, at 4, 6, 8, 12 and 24 h after LPS treatment, lung injury including pathologic histology, lung edema, and inflammation were detected. The optimal time point for lung injury was determined to be 12 h, at which time DEX was added to further test. Furthermore, STAT3 inhibitor (NSC74859) and GSK-3β inhibitor (SB216763) were added to verify the role of STAT3, GSK-3β and NF-κB in ameliorated ALI. Our results show that DEX pretreatment significantly decreased lung Wet-to-Dry weight (W/D) ratio and MPO activity and ameliorated LPS induced lung histopathological alterations. In addition, we confirmed that DEX can increased the phosphorylation of STAT3 and GSK-3β, and inhibit the phosphorylation of nuclear factor-κB (NF-κB) p65 in the inflammatory response induced by LPS. What's more, NSC74859 inhibited the phosphorylation of STAT3 and reversed the protect effect of DEX on LPS. SB216763 inhibited the phosphorylation of NF-κB and reversed the damage effect of LPS and plays the same anti-inflammatory effect as DEX. In summary, our data demonstrated that DEX can ameliorate ALI induced by LPS through GSK-3β/STAT3-NF-κB pathway.

Zhang H ，Sha J ，Feng X ，Hu X ，Chen Y ，Li B ，Fan H ... -  《-》

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

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 (α2-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 α2-ARs instead of IRs.

Chen Y ，Luan L ，Wang C ，Song M ，Zhao Y ，Yao Y ，Yang H ，Ma B ，Fan H ... -  《-》

Dexmedetomidine attenuates ferroptosis by Keap1-Nrf2/HO-1 pathway in LPS-induced acute kidney injury.

Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX's protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.

Luo RR ，Yang J ，Sun YL ，Zhou BY ，Zhou SX ，Zhang GX ，Yang AX ... -  《-》