Dexmedetomidine Alleviates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting p75NTR-Mediated Oxidative Stress and Apoptosis

Abstract

Oxidative stress and apoptosis play a key role in the pathogenesis of sepsis-associated acute kidney injury (AKI). Dexmedetomidine (DEX) may present renal protective effects in sepsis. Therefore, we studied antioxidant effects and the mechanism of DEX in an inflammatory proximal tubular epithelial cell model and lipopolysaccharide- (LPS-) induced AKI in mice. Methods. We assessed renal function (creatinine, urea nitrogen), histopathology, oxidative stress (malondialdehyde (MDA) and superoxide dismutase (SOD)), and apoptosis (TUNEL staining and Cleaved caspase-3) in mice. In vitro experiments including Cleaved caspase-3 and p75NTR/p38MAPK/JNK signaling pathways were evaluated using western blot. Reactive oxidative species (ROS) production and apoptosis were determined using flow cytometry. Results. DEX significantly improved renal function and kidney injury and also revert the substantially increased level of MDA concentrations as well as the reduction of the SOD enzyme activity found in LPS-induced AKI mice. In parallel, DEX treatment also reduced the apoptosis and Cleaved caspase-3 expression evoked by LPS. The expression of p75NTR was increased in kidney tissues of mice with AKI but decreased after treatment with DEX. In cultured human renal tubular epithelial cell line (HK-2 cells), DEX inhibited LPS-induced apoptosis and generation of ROS, but this was reversed by overexpression of p75NTR. Furthermore, pretreatment with DEX significantly downregulated phosphorylation of JNK and p38MAPK in LPS-stimulated HK-2 cells, and this effect was abolished by overexpression of p75NTR. Conclusion. DEX ameliorated AKI in mice with sepsis by partially reducing oxidative stress and apoptosis through regulation of p75NTR/p38MAPK/JNK signaling pathways.

Kidney Organoids as a Novel Platform to Evaluate Lipopolysaccharide-Induced Oxidative Stress and Apoptosis in Acute Kidney Injury

“…Lipopolysaccharide is widely used for SA-AKI induction in mice ( 12 ). We verified its efficacy by injecting 10 mg/kg of LPS (dissolved in 0.9% saline) into mice, intraperitoneally.…”

“…Other studies chose to switch to in vitro experiments to eliminate these potential confounders. Most studies have been carried out using proximal tubular epithelial cells to study the toxicity of LPS ( 12 ). However, the kidney is made up of a variety of cell types, including but not limited to podocytes, proximal tubular cells, loops of Henle cells, distal tubular cells, and collecting duct cells.…”

Association of Apoptosis-Mediated CD4+ T Lymphopenia With Poor Outcome After Type A Aortic Dissection Surgery

“…Inflammatory response has been known as key mechanism underlying aortic dissection. The upregulation of cytokines, endothelial adhesion molecules or chemokines are found to play a role in multiple organ injury, including myocardial ischemic injury, acute kidney injury and gastrointestinal disorders (23)(24)(25)(26)(27)(28). These data led us to speculate that immune cells are important to the postoperative organ injury in AAD patients.…”

METRNL reduced inflammation in sepsis-induced renal injury via PPARδ-dependent pathways

“…There are few epidemiological studies of sepsis-caused AKI. Present studies have shown that its fatality rate is as high as 70%, which is significantly higher than that of sepsis patients without organ damage (Wang et al, 2020). If timely and effective intervention can be implemented in the early stage of AKI in 2015).…”