背景:有效的化学治疗剂顺铂的治疗效用受到其肾毒性作用的阻碍。我们旨在从当前研究中检查氨氯地平通过γ-谷氨酰转肽酶(GGT)酶抑制对顺铂肾毒性的可能保护作用。
方法:氨氯地平(5mg/kg,po)连续14天给予大鼠。在第十天,单剂量顺铂(6.5mg/kg,ip)。在最后一天,收集血样用于评估肾功能,而肾脏样本用于测定GGT活性,氧化应激,炎症,和凋亡标志物,以及组织病理学评估。
结果:氨氯地平可减轻肾损伤,表现为血清肌酐和血尿素氮水平明显降低,与顺铂组相比。氨氯地平抑制GGT酶,参与细胞外谷胱甘肽(GSH)和铂-GSH缀合物与反应性毒性硫醇的代谢。此外,氨氯地平降低了肾脏中NADPH氧化酶的mRNA表达,同时通过激活Nrf2/HO-1信号增强抗氧化防御。此外,它通过减少p38丝裂原活化蛋白激酶(p38MAPK)和核因子-κB(NF-κB)的表达而表现出明显的抗炎反应,随后下调肿瘤坏死因子-α(TNF-α),白细胞介素-6(IL-6),和血管细胞粘附分子-1(VCAM-1)。此外,氨氯地平降低Bax/Bcl-2比值和升高肝细胞生长因子(HGF),因此有利于肾细胞存活。
结论:氨氯地平对GGT的有效抑制与增强抗氧化防御和抑制炎症信号和细胞凋亡相关,支持我们的建议,即氨氯地平可以替代毒性GGT抑制剂来对抗顺铂肾毒性。
BACKGROUND: The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity.
METHODS: Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation.
RESULTS: Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival.
CONCLUSIONS: Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.