Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Campus, 369 Fulham Rd, London SW10 9NH, UK.
Crit Care. 2011 Jun 24;15(3):R153. doi: 10.1186/cc10283.
Acute kidney injury following surgery incurs significant mortality with no proven preventative therapy. We investigated whether the α2 adrenoceptor agonist dexmedetomidine (Dex) provides protection against ischemia-reperfusion induced kidney injury in vitro and in vivo.
In vitro, a stabilised cell line of human kidney proximal tubular cells (HK2) was exposed to culture medium deprived of oxygen and glucose. Dex decreased HK2 cell death in a dose-dependent manner, an effect attenuated by the α2 adrenoceptor antagonist atipamezole, and likely transduced by phosphatidylinositol 3-kinase (PI3K-Akt) signaling. In vivo C57BL/6J mice received Dex (25 μg/kg, intraperitoneal (i.p.)) 30 minutes before or after either bilateral renal pedicle clamping for 25 minutes or right renal pedicle clamping for 40 minutes and left nephrectomy.
Pre- or post-treatment with Dex provided cytoprotection, improved tubular architecture and function following renal ischemia. Consistent with this cytoprotection, dexmedetomidine reduced plasma high-mobility group protein B1 (HMGB-1) elevation when given prior to or after kidney ischemia-reperfusion; pretreatment also decreased toll-like receptor 4 (TLR4) expression in tubular cells. Dex treatment provided long-term functional renoprotection, and even increased survival following nephrectomy.
Our data suggest that Dex likely activates cell survival signal pAKT via α2 adrenoceptors to reduce cell death and HMGB1 release and subsequently inhibits TLR4 signaling to provide reno-protection.
手术后发生的急性肾损伤会导致很高的死亡率，且目前尚无有效的预防疗法。我们研究了 α2 肾上腺素受体激动剂右美托咪定（Dex）是否能在体外和体内预防缺血再灌注引起的肾损伤。
在体外，将人肾近端小管细胞（HK2）的稳定细胞系暴露于缺氧和无糖的培养基中。Dex 以剂量依赖的方式减少 HK2 细胞死亡，这种作用被 α2 肾上腺素受体拮抗剂阿替美唑减弱，可能通过磷酸肌醇 3-激酶（PI3K-Akt）信号转导。在体内，C57BL/6J 小鼠在双侧肾蒂夹闭 25 分钟或右肾蒂夹闭 40 分钟并左肾切除前 30 分钟或后 30 分钟接受 Dex（25μg/kg，腹腔内（i.p.））。
Dex 的预处理或后处理在肾缺血后提供了细胞保护作用，改善了肾小管结构和功能。与这种细胞保护作用一致，Dex 在给予肾缺血再灌注前或后降低了血浆高迁移率族蛋白 B1（HMGB-1）的升高；预处理还降低了肾小管细胞中 Toll 样受体 4（TLR4）的表达。Dex 治疗提供了长期的肾功能保护作用，甚至在肾切除后增加了存活率。
我们的数据表明，Dex 可能通过 α2 肾上腺素受体激活细胞存活信号 pAKT 来减少细胞死亡和 HMGB1 释放，随后抑制 TLR4 信号转导，从而提供肾保护作用。
Zotero 插件
