Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India.
National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
Toxicol Appl Pharmacol. 2014 May 15;277(1):8-20. doi: 10.1016/j.taap.2014.02.022. Epub 2014 Mar 14.
Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in the kidney.
庆大霉素诱导的肾毒性已有充分的文献记载，但其潜在的机制和预防策略仍有待研究。本研究旨在探讨柚皮苷（一种生物类黄酮）对庆大霉素诱导的肾毒性的保护作用，并阐明其潜在的机制。通过评估血清特定肾功能参数（血尿素氮和肌酐）和肾脏组织的组织病理学，来评估庆大霉素引起的肾毒性。还评估了肾脏氧化应激（脂质过氧化、蛋白质羰基化、酶和非酶抗氧化剂）、炎症（NF-κB[p65]、TNF-α、IL-6 和 MPO）和细胞凋亡（caspase 3、caspase 9、Bax、Bcl-2、p53 和 DNA 片段化）标志物。线粒体 NADH 脱氢酶、琥珀酸脱氢酶、细胞色素 c 氧化酶和线粒体氧化还原活性的显著下降表明庆大霉素诱导的线粒体功能障碍。柚皮苷（100mg/kg）治疗联合庆大霉素恢复了线粒体功能，增加了肾脏内源性抗氧化状态。庆大霉素诱导的肾炎症细胞因子（TNF-α和 IL-6）增加，核蛋白表达 NF-κB（p65）和 NF-κB-DNA 结合活性以及髓过氧化物酶（MPO）活性，经柚皮苷治疗后显著降低。此外，柚皮苷治疗还显著降低了 cleaved caspase 3、Bax 和 p53 蛋白表达的量，并增加了 Bcl-2 蛋白表达。柚皮苷治疗还改善了肾组织损伤的程度，并减少了肾小管中的炎症浸润。U-HPLS-MS 数据显示，与庆大霉素联合使用柚皮苷并没有改变肾脏对庆大霉素的摄取和/或在肾脏组织中的积累。这些发现表明，柚皮苷治疗通过减轻氧化应激、线粒体功能障碍、炎症和细胞凋亡，减轻了肾脏的功能障碍和结构损伤。
