Department of Anesthesiology and Intensive Care, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima Prefecture, 890-0075, Japan.
Department of Anesthesiology and Intensive Care, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima Prefecture, 890-0075, Japan.
Biomed Pharmacother. 2020 May;125:109912. doi: 10.1016/j.biopha.2020.109912. Epub 2020 Jan 31.
To investigate the mechanisms through which dexmedetomidine (DEX) could improve the renal injury in lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and examine how TNF-α or DEX might affect mitochondrial function and renal injury.
In vivo experiments involved 24 rats randomly allocated to a sham group, an LPS group, and an LPS + DEX group. Serum creatinine, lactate, TNF-α, IL-1β, and IL-6 concentrations, as well as urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, were measured 0, 3, and 6 h after the start of the experiments. Histopathological examinations were performed to determine the extent of LPS-induced renal injury and recovery by administration of DEX. in vitro, human embryonic kidney 293 cells were treated with or without (control) several concentrations of TNF-α and DEX for 24 h before measurements of the oxygen consumption rate (OCR) under basal conditions and with the addition of oligomycin, carbonylcyanide-p-trifluoromethoxyphenylhydrazone, antimycin A, and rotenone, as well as intracellular reactive oxygen species (ROS) levels.
DEX attenuated LPS-induced increases in serum creatinine and IL-6 concentrations. LPS administration caused histological tissue damage in the kidney, but DEX prevented such damage. In vitro, DEX suppressed TNF-α-induced increases in basal OCR and ROS levels and inhibited decreases of ATP production induced by TNF-α.
DEX has protective effects for cells and tissues of the kidney by inhibiting oxygen consumption and hypoxia or by improving mitochondrial dysfunction via TNF-α in the renal cells. These results might point to DEX being an important new therapeutic target for the treatment of septic AKI.
研究右美托咪定（DEX）改善脂多糖（LPS）诱导的急性肾损伤（AKI）中肾损伤的机制，并探讨 TNF-α或 DEX 如何影响线粒体功能和肾损伤。
体内实验涉及 24 只大鼠，随机分为假手术组、LPS 组和 LPS+DEX 组。实验开始后 0、3 和 6 h 时测定血清肌酐、乳酸、TNF-α、IL-1β和 IL-6 浓度以及尿 8-羟基-2'-脱氧鸟苷（8-OHdG）水平。通过给予 DEX 观察 LPS 诱导的肾损伤的程度和恢复情况进行组织病理学检查。体外，人胚肾 293 细胞用或不用（对照）几种浓度的 TNF-α和 DEX 处理 24 h，然后测量基础状态下和加入寡霉素、羰基氰化物-p-三氟甲氧基苯腙、抗霉素 A 和鱼藤酮后的耗氧量（OCR）以及细胞内活性氧（ROS）水平。
DEX 减轻了 LPS 诱导的血清肌酐和 IL-6 浓度升高。LPS 给药导致肾脏组织损伤，但 DEX 可预防这种损伤。在体外，DEX 抑制了 TNF-α诱导的基础 OCR 和 ROS 水平升高，并抑制了 TNF-α诱导的 ATP 产生减少。
DEX 通过抑制氧消耗和缺氧，或通过 TNF-α改善肾细胞中的线粒体功能障碍，对肾脏细胞和组织具有保护作用。这些结果可能表明 DEX 是治疗脓毒症 AKI 的一个重要新的治疗靶点。
