Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 215008 Suzhou, Jiangsu, China.
Suzhou Clinical Medical Center of Critical Care Medicine, 215001 Suzhou, Jiangsu, China.
Front Biosci (Landmark Ed). 2023 Dec 1;28(12):323. doi: 10.31083/j.fbl2812323.
Dexmedetomidine (DEX) reportedly protects against ischemia-reperfusion (I/R) injury and associated damage to the kidneys, but the underlying mechanisms have yet to be established.
Unilateral nephrectomy was performed in Wistar rats, and the remaining kidney was clamped for 1 h prior to reperfusion to establish an experimental model system. These animals were then randomized into Sham, DEX + Sham, DEX + I/R, ATI (Altepamizole, α2-adrenergic receptor inhibitor) + DEX + I/R, and 3-MA (3-methyladenine, autophagy inhibitor) + DEX + I/R groups. Serum renal function biomarkers, acute kidney injury (AKI) histopathological scores, serum inflammatory factors, redox biomarkers, markers of autophagic flux, and autophagosome numbers were assessed. Levels of proteins related to the autophagic pathway, including mTOR and AMPK, were also analyzed.
Serum creatinine and urea nitrogen levels in the I/R group were significantly elevated over those in sham control rats, as were AKI scores, serum inflammatory cytokine concentrations (IL-6, IL-1β, and TNF-α), and serum levels of the oxidative stress biomarker malondialdehyde (MDA). All of these parameters were significantly reduced in the DEX + I/R group relative to I/R model rats. I/R group rats also exhibited significant decreases in renal levels of autophagic flux-related biomarkers and autophagosome numbers relative to sham controls, while DEX administration partially restored normal autophagic flux in these rats. Acute I/R also suppress the expression of AMPK in the kidney while increasing mTOR expression, and DEX reversed these effects. The beneficial impact of DEX on I/R-associated AKI was ablated by ATI or 3-MA administration.
These analyses provide strong evidence for the ability of DEX to protect against I/R-associated AKI the α2-AR/AMPK/mTOR pathway-mediated enhancement of autophagic activity.
右美托咪定（DEX）据报道可预防缺血再灌注（I/R）损伤和相关的肾脏损伤，但潜在机制尚未确定。
对 Wistar 大鼠进行单侧肾切除术，在再灌注前将剩余的肾脏夹闭 1 小时，建立实验模型系统。这些动物随后被随机分为假手术（Sham）、DEX+Sham、DEX+I/R、ATI（Altepamizole，α2-肾上腺素能受体抑制剂）+DEX+I/R 和 3-MA（3-甲基腺嘌呤，自噬抑制剂）+DEX+I/R 组。评估血清肾功能生物标志物、急性肾损伤（AKI）组织病理学评分、血清炎症因子、氧化还原生物标志物、自噬流标志物和自噬体数量。还分析了与自噬途径相关的蛋白水平，包括 mTOR 和 AMPK。
与 Sham 对照组相比，I/R 组的血清肌酐和尿素氮水平显著升高，AKI 评分、血清炎症细胞因子浓度（IL-6、IL-1β 和 TNF-α）和血清氧化应激生物标志物丙二醛（MDA）水平也显著升高。与 I/R 模型大鼠相比，DEX+I/R 组这些参数均显著降低。I/R 组大鼠肾组织自噬流相关标志物和自噬体数量也明显减少，而 DEX 给药部分恢复了这些大鼠的正常自噬流。急性 I/R 还抑制了肾脏中 AMPK 的表达，同时增加了 mTOR 的表达，DEX 逆转了这些效应。ATI 或 3-MA 给药削弱了 DEX 对 I/R 相关 AKI 的有益影响。
这些分析为 DEX 预防 I/R 相关 AKI 的能力提供了有力证据，其机制可能与通过α2-AR/AMPK/mTOR 途径增强自噬活性有关。
