Department of Medical Periodical Press, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Mol Med Rep. 2020 Mar;21(3):1597-1605. doi: 10.3892/mmr.2020.10962. Epub 2020 Jan 24.
Cisplatin (CP) is an effective antineoplastic agent; however, CP‑induced acute kidney injury (AKI) seriously affects the prognosis of patients with cancer. Endoplasmic reticulum (ER) stress (ERS)‑induced apoptosis serves a pivotal role in the pathogenesis of CP‑induced AKI. Dexmedetomidine (Dex), a potent α2 adrenergic agonist, has been reported to exert protective effects against AKI. However, the protective effects of Dex against CP‑induced AKI and the potential molecular mechanisms remain unknown. In the present study, male Sprague‑Dawley rats were divided into four groups (n=10/group), as follows: Control group; CP group, rats received an intraperitoneal (i.p.) injection of 5 mg/kg CP; Dex + CP group, rats received an i.p. injection of 25 µg/kg Dex immediately after CP treatment; and Dex + CP + atipamezole (Atip) group, rats received an i.p. injection of 250 µg/kg Atip, an α2 adrenoreceptor (α2AR) antagonist, and then received the same treatment as the Dex + CP group. Rats were anesthetized and sacrificed 96 h after CP injection. Subsequently, serum blood urea nitrogen (BUN) and serum creatinine (Scr) were analyzed, and kidney samples were collected for analyses. Pathological changes were examined using hematoxylin and eosin staining, and protein expression levels were assessed using western blotting and immunohistochemical staining. In addition, apoptosis was examined using a terminal deoxynucleotidyl transferase dUTP nick‑end labeling assay. The present results suggested that Dex protected against CP‑induced AKI by attenuating histological changes in the kidney, serum BUN and Scr production. Furthermore, the expression levels of 78‑kDa glucose‑regulated protein, C/EBP homologous protein and caspase‑12, and the apoptotic rate in the kidney were decreased following Dex treatment. In addition, the expression levels of phosphorylated (p)‑PI3K and p‑AKT in the Dex + CP group were significantly increased. Conversely, the renoprotective effects of Dex were attenuated following the addition of Atip. In conclusion, Dex may alleviate CP‑induced AKI by attenuating ERS‑induced apoptosis, at least in part, via the α2AR/PI3K/AKT signaling pathway.
顺铂（CP）是一种有效的抗肿瘤药物；然而，CP 诱导的急性肾损伤（AKI）严重影响癌症患者的预后。内质网（ER）应激（ERS）诱导的细胞凋亡在 CP 诱导的 AKI 发病机制中起关键作用。右美托咪定（Dex），一种有效的 α2 肾上腺素能激动剂，已被报道可发挥对 AKI 的保护作用。然而，Dex 对 CP 诱导的 AKI 的保护作用及其潜在的分子机制尚不清楚。在本研究中，雄性 Sprague-Dawley 大鼠分为四组（每组 10 只），如下所示：对照组；CP 组，大鼠接受腹腔（i.p.）注射 5mg/kg CP；Dex+CP 组，大鼠在 CP 处理后立即接受 i.p.注射 25μg/kg Dex；Dex+CP+Atipamezole（Atip）组，大鼠接受 i.p.注射 250μg/kg Atip，一种 α2 肾上腺素受体（α2AR）拮抗剂，然后接受与 Dex+CP 组相同的治疗。大鼠在 CP 注射后 96h 麻醉并处死。随后，分析血清血尿素氮（BUN）和血清肌酐（Scr），并收集肾脏样本进行分析。使用苏木精和伊红染色检查病理变化，使用 Western blot 和免疫组织化学染色检查蛋白表达水平。此外，使用末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测法检查细胞凋亡。本研究结果表明，Dex 通过减轻肾脏组织学变化、血清 BUN 和 Scr 产生来保护 CP 诱导的 AKI。此外，Dex 处理后，肾脏中 78kDa 葡萄糖调节蛋白、C/EBP 同源蛋白和胱天蛋白酶-12 的表达水平以及细胞凋亡率降低。此外，Dex+CP 组中磷酸化（p）-PI3K 和 p-AKT 的表达水平显著增加。相反，添加 Atip 后 Dex 的肾保护作用减弱。综上所述，Dex 通过减轻 ERS 诱导的细胞凋亡来缓解 CP 诱导的 AKI，至少部分通过 α2AR/PI3K/AKT 信号通路。
