Abstract

Cyclophosphamide (CP) is widely used as a chemotherapy against various types of cancers. However, CP is accompanied with multiple organ toxicity due to production of reactive oxygen species (ROS), induction of inflammation and consequently apoptosis. Alogliptin (Alo) is a dipeptidyl peptidase 4 (DPP-IV) inhibitor, which is booming as an antidiabetic agent. Interestingly, gliptins are currently studied for their counter-regulatory effects against oxidative stress and inflammation via multiple pathways, among which is the mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway. This cascade can reduce inflammation via mitigating the activity of mothers against decapentaplegic homolog 3 (SMAD3) and c-Jun. However, Alo effect against CP-induced kidney injury has not been previously elucidated. This tempted us to investigate the possible beneficial effect of Alo against CP-induced kidney injury via modulating the MAP3K/JNK/SMAD3 signaling cascade. Thirty-two male Wistar rats were randomly allocated into four groups. CP-treated group received a single dose of CP (200 mg/kg; i.p.). Alo-treated group received Alo (20 mg/kg/day; p.o.) for 7 days with single CP injection on day 2. Marked decrease in renal injury was observed upon Alo treatment, as evidenced through declined serum kidney function markers, oxidative stress and apoptosis markers, MAP3K expression, phospho (p)-SMAD3, p-JNK, and p-c-Jun levels. These cellular effects were reflected in reduced transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α) fibrotic and inflammatory mediators, coinciding with improved histopathological portrait. In conclusion, the current study provides novel application of Alo as a therapeutic modality against CP-induced nephrotoxicity.

摘要

环磷酰胺（CP）被广泛用作针对各种癌症的化学疗法。然而，由于活性氧（ROS）的产生、炎症的诱导和随后的细胞凋亡，CP伴随着多器官毒性。阿格列汀 (Alo) 是一种二肽基肽酶 4 (DPP-IV) 抑制剂，作为一种抗糖尿病药物正在蓬勃发展。有趣的是，目前正在研究 gliptins 通过多种途径对抗氧化应激和炎症的反调节作用，其中包括丝裂原活化蛋白激酶 (MAPK)/c-Jun N-末端激酶 (JNK) 途径。这种级联反应可以通过减轻母亲对 decapentaplegic 同源物 3 (SMAD3) 和 c-Jun 的活性来减轻炎症。然而，Alo 对 CP 引起的肾损伤的作用以前尚未阐明。这促使我们通过调节 MAP3K/JNK/SMAD3 信号级联来研究 Alo 对 CP 诱导的肾损伤的可能有益作用。将 32 只雄性 Wistar 大鼠随机分为四组。CP 治疗组接受单剂量 CP (200 mg/kg；ip)。Alo 治疗组接受 Alo（20 mg/kg/天；口服）7 天，第 2 天单次 CP 注射。Alo 治疗后观察到肾损伤显着减轻，血清肾功能标志物下降、氧化应激和凋亡标志物、MAP3K 表达、磷酸化 (p)-SMAD3、p-JNK 和 pc-Jun 水平。这些细胞效应反映在转化生长因子 β (TGF-β) 和肿瘤坏死因子 α (TNF-α) 纤维化和炎症介质的减少，与组织病理学图像的改善相吻合。综上所述，