Abdoli Narges, Sadeghian Issa, Mousavi Khadijeh, Azarpira Negar, Ommati Mohammad Mehdi, Heidari Reza
Iran Food and Drug Administration, Ministry of Health, Tehran, Iran.
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Curr Res Pharmacol Drug Discov. 2020 Oct 13;1:30-38. doi: 10.1016/j.crphar.2020.100006. eCollection 2020 Apr.
Cirrhosis-induced renal injury or cholemic nephropathy (CN) is a serious clinical complication with poor prognosis. CN could finally lead to renal failure and the need for organ transplantation. Unfortunately, there is no specific pharmacological intervention against CN to date. On the other hand, various studies mentioned the role of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to evaluate the potential protective effects of NAC as a thiol-reducing agent and antioxidant in CN. Bile duct ligation (BDL) was used as a reliable animal model of cholestasis. BDL animals received NAC (0.25% and 1% w: v) in drinking water for 28 consecutive days. Finally, urine, blood, and kidney samples were collected and analyzed. Significant elevation in serum biomarkers of renal injury, along with urine markers of kidney damage, was evident in the BDL group. Moreover, markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, and increased oxidized glutathione (GSSG) were evident detected in the kidney of cholestatic rats. Renal tissue antioxidant capacity and reduced glutathione (GSH) were also significantly depleted in the BDL group. Significant mitochondrial depolarization, depleted ATP content, and mitochondrial permeabilization was also detected in mitochondria isolated from the kidney of cholestatic animals. Renal histopathological alterations consisted of significant tissue fibrosis, interstitial inflammation, and tubular atrophy. It was found that NAC (0.25 and 1% in drinking water for 28 consecutive days) blunted histopathological changes, decreased markers of oxidative stress, and improved mitochondrial indices in the kidney of cirrhotic rats. Moreover, serum and urine biomarkers of renal injury were also mitigated in upon NAC treatment. These data indicate a potential renoprotective role for NAC in cholestasis. The effects of NAC on cellular redox state and mitochondrial function seem to play a fundamental role in its renoprotective effects during CN.
肝硬化所致肾损伤或胆汁血症肾病（CN）是一种预后不良的严重临床并发症。CN最终可导致肾衰竭并需要进行器官移植。不幸的是，迄今为止尚无针对CN的特异性药物干预措施。另一方面，多项研究提及氧化应激和线粒体损伤在CN发病机制中的作用。本研究旨在评估N - 乙酰半胱氨酸（NAC）作为一种巯基还原剂和抗氧化剂在CN中的潜在保护作用。胆管结扎（BDL）被用作胆汁淤积的可靠动物模型。BDL动物连续28天饮用含NAC（0.25%和1% w:v）的水。最后，收集并分析尿液、血液和肾脏样本。BDL组中，肾损伤血清生物标志物以及肾损伤尿液标志物显著升高。此外，在胆汁淤积大鼠的肾脏中明显检测到氧化应激标志物，包括活性氧（ROS）生成、脂质过氧化、蛋白质羰基化以及氧化型谷胱甘肽（GSSG）增加。BDL组肾组织抗氧化能力和还原型谷胱甘肽（GSH）也显著减少。在从胆汁淤积动物肾脏分离的线粒体中还检测到明显的线粒体去极化、ATP含量减少和线粒体通透性增加。肾脏组织病理学改变包括显著的组织纤维化、间质炎症和肾小管萎缩。研究发现，NAC（连续28天在饮用水中添加0.25%和1%）可减轻肝硬化大鼠肾脏的组织病理学变化，降低氧化应激标志物，并改善线粒体指标。此外，NAC治疗后肾损伤的血清和尿液生物标志物也有所减轻。这些数据表明NAC在胆汁淤积中具有潜在的肾脏保护作用。NAC对细胞氧化还原状态和线粒体功能的影响似乎在其对CN的肾脏保护作用中发挥着重要作用。
