Department of Nephrology, Yi Ji Shan Hospital affiliated to Wan Nan Medical College, Wuhu, 241000, China.
Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wan Nan Medical College, Wuhu, 241000, China.
Curr Med Sci. 2022 Jun;42(3):505-512. doi: 10.1007/s11596-022-2516-5. Epub 2022 Jun 8.
Ticagrelor is a widely used anti-platelet drug. However, the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury (AKI) have not been clearly demonstrated. We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.
C57BL6J mice received oral ticagrelor (20 mg/kg and 50 mg/kg) for 7 days, and then caecal ligation and puncture (CLP) were performed. An adenosine receptor antagonist, CGS15943, was administered (10 mg/kg, intraperitoneal injection) to block the adenosine pathway 2 h before CLP. After 24 h, serum creatinine levels were measured. Periodic acid-Schiff (PAS) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were employed to analyze pathological changes and cell apoptosis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and mRNA expression of tissue TNF-α and IL-1β were detected. Western blotting analysis was used to determine AKT and mammalian target of rapamycin (mTOR) protein expression in the kidney.
PAS staining showed less swelling of renal tubules, and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group. Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group. Moreover, significantly lower serum and kidney levels of TNF-α and IL-1β were observed in the ticagrelor group. CGS15943 blocked the effects of ticagrelor. Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group. The adenosine receptor antagonist inhibited the activation of AKT and mTOR.
This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.
替格瑞洛是一种广泛应用的抗血小板药物。然而，替格瑞洛对脓毒症诱导的急性肾损伤（AKI）的保护作用机制尚未明确。本研究旨在探讨替格瑞洛对脓毒症诱导的 AKI 的保护作用及其潜在机制。
C57BL6J 小鼠连续 7 天口服替格瑞洛（20mg/kg 和 50mg/kg），然后进行盲肠结扎穿孔（CLP）。在 CLP 前 2 小时，给予腺苷受体拮抗剂 CGS15943（10mg/kg，腹腔注射）阻断腺苷途径。24 小时后，测定血清肌酐水平。采用过碘酸希夫（PAS）染色和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）染色分析病理变化和细胞凋亡。检测血清肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）浓度及组织 TNF-α和 IL-1βmRNA 表达。采用 Western blot 分析检测肾脏 AKT 和哺乳动物雷帕霉素靶蛋白（mTOR）的蛋白表达。
PAS 染色显示替格瑞洛组肾小管肿胀减轻，TUNEL 染色显示细胞凋亡减少。与 CLP 组相比，替格瑞洛组血清肌酐水平显著降低。此外，替格瑞洛组血清和肾脏 TNF-α和 IL-1β水平均显著降低。CGS15943 阻断了替格瑞洛的作用。Western blot 分析显示，50mg/kg 替格瑞洛组肾脏 AKT 和 mTOR 磷酸化增加。腺苷受体拮抗剂抑制了 AKT 和 mTOR 的激活。
本研究表明，替格瑞洛对脓毒症诱导的 AKI 的保护作用依赖于腺苷受体的激活，以及随后 AKT 和 mTOR 磷酸化的增加。
