National Center for Trauma Medicine, Ministry of Education Key Laboratory of Trauma and Neural Regeneration, Trauma Medicine Center, Peking University People's Hospital, Beijing, China.
Ren Fail. 2023 Dec;45(1):2189482. doi: 10.1080/0886022X.2023.2189482.
Ischemic postconditioning (I-PostC) has a protective effect against acute kidney injury (AKI) induced by limb ischemia-reperfusion (LIR); however, the exact mechanism remains to be elucidated. Our study aims to investigate the potential involvement of high-mobility group box 1 protein (HMGB1) and autophagy in renoprotection generated by I-PostC. A rat model of LIR-induced AKI was established and rats were randomly assigned to five groups: (i) sham-operated control, (ii) I/R, (iii) I/R + I-PostC, (iv) I/R + I-PostC + rapamycin (autophagy activator), and (v) I/R + I-PostC + 3-methyladenine (autophagy inhibitor). Morphological changes in the kidneys were assessed by histology, and ultrastructural changes in renal tubular epithelial cells and glomerular podocytes were observed by transmission electron microscopy. The levels of kidney function parameters, serum inflammatory factors, and autophagy markers were detected. The results showed that the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines (TNF-α and IL-6) were significantly higher in the I/R group compared to the sham control in serum and in renal tissues. I-PostC significantly reduced the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines in renal tissues and improved renal function. Renal histopathology and ultrastructural observations indicated that I-PostC alleviated renal tissue injury. In addition, rapamycin (autophagy activator) treatment increased the levels of inflammatory cytokine expression levels and decreased renal function, reversed the protective effect of I-PostC against LIR-induced AKI. In conclusion, I-PostC could play a protective role against AKI by regulating the release of HMGB1 and inhibiting autophagy activation.
缺血后处理（I-PostC）对肢体缺血再灌注（LIR）引起的急性肾损伤（AKI）具有保护作用；然而，其确切机制仍有待阐明。本研究旨在探讨高迁移率族蛋白 B1（HMGB1）和自噬在 I-PostC 产生的肾保护作用中的潜在作用。建立了大鼠 LIR 诱导的 AKI 模型，将大鼠随机分为五组：（i）假手术对照，（ii）I/R，（iii）I/R+I-PostC，（iv）I/R+I-PostC+雷帕霉素（自噬激活剂）和（v）I/R+I-PostC+3-甲基腺嘌呤（自噬抑制剂）。通过组织学评估肾脏的形态变化，通过透射电子显微镜观察肾小管上皮细胞和肾小球足细胞的超微结构变化。检测肾功能参数、血清炎症因子和自噬标志物的水平。结果显示，与 sham 对照组相比，I/R 组血清和肾组织中 HMGB1、Beclin1、LC3-II/LC3-I 和炎症因子（TNF-α和 IL-6）水平显著升高。I-PostC 显著降低了肾组织中 HMGB1、Beclin1、LC3-II/LC3-I 和炎症因子的水平，改善了肾功能。肾组织病理学和超微结构观察表明，I-PostC 减轻了肾组织损伤。此外，雷帕霉素（自噬激活剂）治疗增加了炎症因子表达水平，降低了肾功能，逆转了 I-PostC 对 LIR 诱导的 AKI 的保护作用。总之，I-PostC 通过调节 HMGB1 的释放和抑制自噬激活来发挥对 AKI 的保护作用。
