Tambe Prasad Kisan, Shetty Maya P, Rana Komal, Bharati Sanjay
Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Manipal Government of Karnataka Bioincubator Advanced Research Centre, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Oxid Med Cell Longev. 2025 Mar 6;2025:8892026. doi: 10.1155/omcl/8892026. eCollection 2025.
The present study reports the protective effect conferred by scavenging mitochondrial oxidative stress (mtOS) in 5-fluorouracil (5-FU)-induced renal injury. 5-FU renal toxicity model was created by administering 5-FU (12 mg/kg b.w. intraperitoneally [i.p.], for 4 days) to male BALB/c mice. The protective effect of mitochondria-targeted antioxidant (MTA), Mito-TEMPO coadministered at a dosage of 0.1 mg/kg b.w. i.p., was established in terms of levels/expressions of renal injury markers, histopathological alterations, oxidative DNA damage, proinflammatory markers, mtOS, mitochondrial dysfunction, and modulation of apoptotic proteins and apoptotic cell death. A significant rise in the levels of serum urea, uric acid, and creatinine was noted after 5-FU administration to the animals. Immunohistochemical and ELISA findings demonstrated significant decrease in podocin and conversely a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) expression after 5-FU challenge. The histopathological analysis further revealed Bowman's capsule dilation, glomerular condensation, and vacuolar degeneration. Mito-TEMPO treatment significantly lowered renal injury markers, reversed the expressions of podocin and NGAL to normal, and restored normal histoarchitecture of renal tissue. Mitochondrial reactive oxygen species (mtROS), mtLPO, activity of mitochondrial enzyme complexes, and mitochondrial antioxidant defense status were significantly improved in Mito-TEMPO protected group as compared to the 5-FU group. Further, significantly decreased expression of 8-OHdG, reduction in apoptotic cell death, and modulation of apoptotic proteins Bax, Bcl-2, and caspase-3 were noted in Mito-TEMPO protected group, indicating its protective effect against 5-FU-induced renal injury. The approach of targeting mtOS using MTA, Mito-TEMPO, may prove as safe adjuvant in alleviating renal toxicity during 5-FU chemotherapy.
本研究报告了清除线粒体氧化应激（mtOS）对5-氟尿嘧啶（5-FU）诱导的肾损伤的保护作用。通过给雄性BALB/c小鼠腹腔注射5-FU（12mg/kg体重，连续4天）建立5-FU肾毒性模型。从肾损伤标志物的水平/表达、组织病理学改变、氧化性DNA损伤、促炎标志物、mtOS、线粒体功能障碍以及凋亡蛋白和凋亡细胞死亡的调节等方面，确定了腹腔注射剂量为0.1mg/kg体重的线粒体靶向抗氧化剂（MTA）Mito-TEMPO的保护作用。给动物注射5-FU后，血清尿素、尿酸和肌酐水平显著升高。免疫组织化学和酶联免疫吸附测定结果表明，5-FU攻击后足突蛋白显著减少，相反，中性粒细胞明胶酶相关脂质运载蛋白（NGAL）表达显著增加。组织病理学分析进一步显示肾小囊扩张、肾小球浓缩和空泡变性。Mito-TEMPO治疗显著降低了肾损伤标志物，使足突蛋白和NGAL的表达恢复正常，并恢复了肾组织的正常组织结构。与5-FU组相比，Mito-TEMPO保护组的线粒体活性氧（mtROS）、线粒体脂质过氧化（mtLPO）、线粒体酶复合物活性和线粒体抗氧化防御状态显著改善。此外，Mito-TEMPO保护组中8-羟基脱氧鸟苷（8-OHdG）的表达显著降低，凋亡细胞死亡减少，凋亡蛋白Bax、Bcl-2和半胱天冬酶-3得到调节，表明其对5-FU诱导的肾损伤具有保护作用。使用MTA（Mito-TEMPO）靶向mtOS的方法可能被证明是一种安全的佐剂，可减轻5-FU化疗期间的肾毒性。
