Biotechnology Division, Lupin Limited, Pune, India.
Faculty of Health Sciences, Symbiosis School of Biological Sciences, Symbiosis International (Deemed) University, Pune, India.
J Biochem Mol Toxicol. 2022 Apr;36(4):e22990. doi: 10.1002/jbt.22990. Epub 2022 Feb 17.
In cisplatin-induced nephrotoxicity, the significant role of activation of inflammatory pathways has been reported earlier. Studies indicate elevated expression and activity of tumor necrosis factor-α (TNF-α) in both, serum and kidneys of cisplatin-treated animals. Golimumab, an anti-TNF biologic, has been approved for the management of many inflammatory conditions. This experiment was planned and executed to evaluate the impact of golimumab on renal function, inflammation in cisplatin-induced nephrotoxicity in mice, and oxidative stress. Cisplatin (22 mg/kg) as a single intraperitoneal injection was used to induce nephrotoxicity in mice. Golimumab was administered at 24 mg/kg for 7 days by subcutaneous route. Pentoxifylline (PTX) was administered for 7 days (150 mg/kg) as a reference standard. Renal functions, oxidative stress, and inflammation were evaluated on the seventh day. Cisplatin administration in mice caused a significant rise in serum cystatin C, creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. A significant rise of urinary clusterin, kidney injury molecule-1, and β-N-acetylglucosaminidase levels was also seen in cisplatin-treated animals. Furthermore, cisplatin-induced nephrotoxicity was associated with a significant increase in oxidative stress and inflammation in serum and kidneys. Golimumab treatment significantly prevented the cisplatin-induced alteration in markers of renal function and renal damage. There was a significant reduction in oxidative stress and inflammation in golimumab-treated animals. Furthermore, the histopathological evaluation also revealed inverted changes in the proximal tubules after golimumab treatment in kidneys after cisplatin toxicity. The standard drug, PTX, also prevented nephrotoxicity caused by cisplatin as indicated by the recovery in renal function, reduction in oxidative stress and inflammation. These results indicate that golimumab was effective in nephrotoxicity induced by cisplatin through inhibition of oxidative stress, and inflammatory response.
在顺铂诱导的肾毒性中，炎症途径的激活作用已被早期报道。研究表明，肿瘤坏死因子-α（TNF-α）在顺铂处理动物的血清和肾脏中均有升高的表达和活性。戈利木单抗是一种抗 TNF 的生物制剂，已被批准用于许多炎症性疾病的治疗。本实验旨在评估戈利木单抗对顺铂诱导的肾毒性小鼠肾功能、炎症和氧化应激的影响。顺铂（22mg/kg）腹腔单次注射用于诱导小鼠肾毒性。戈利木单抗按 24mg/kg 皮下给药 7 天。己酮可可碱（PTX）作为参考标准，按 150mg/kg 给药 7 天。第 7 天评估肾功能、氧化应激和炎症。顺铂给药导致小鼠血清胱抑素 C、肌酐、血尿素氮和中性粒细胞明胶酶相关脂质运载蛋白显著升高。顺铂处理动物的尿 clusterin、肾损伤分子-1 和 β-N-乙酰氨基葡萄糖苷酶水平也显著升高。此外，顺铂诱导的肾毒性与血清和肾脏中氧化应激和炎症的显著增加有关。戈利木单抗治疗可显著预防顺铂诱导的肾功能和肾损伤标志物改变。戈利木单抗治疗动物的氧化应激和炎症显著减少。此外，组织病理学评估还显示，顺铂毒性后，戈利木单抗治疗的肾脏近端小管发生反转变化。标准药物 PTX 也可预防顺铂引起的肾毒性，表现为肾功能恢复、氧化应激和炎症减少。这些结果表明，戈利木单抗通过抑制氧化应激和炎症反应，对顺铂诱导的肾毒性有效。
