Peerapanyasut Wachirasek, Kobroob Anongporn, Palee Siripong, Chattipakorn Nipon, Wongmekiat Orawan
Renal Physiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Division of Physiology, School of Medical Science, University of Phayao, Phayao, Thailand.
IUBMB Life. 2020 Apr;72(4):758-770. doi: 10.1002/iub.2175. Epub 2019 Oct 6.
Exposure to bisphenol A (BPA), a chemical generally used in consumer products, becomes a global public health concern, as humans are increasingly exposed through their daily consuming activities. Renal ischemia-reperfusion (RIR) is the major cause of acute kidney injury with high prevalence and increased long-term risks for multiple comorbidities and mortality. As the kidney is susceptible to these conditions, we explored whether the outcomes following the RIR episode could be influenced by BPA exposure, and investigated the therapeutic possibility by N-acetylcysteine (NAC) including the mechanisms involved. Three groups of male Wistar rats were fed with vehicle, BPA 5, and 50 mg/kg, respectively, for five consecutive weeks then underwent the sham operation. Three other groups with identical treatment underwent bilateral renal IR induction (45-min ischemia followed by 24-hr reperfusion). An additional RIR group was treated with BPA 50 plus NAC 100 mg/kg. BPA-exposed rats that encountered RIR episode showed dose-dependent worsening of RIR injury as evidenced by augmentations of renal dysfunction and histopathological abnormalities, oxidative stress, apoptosis, mitochondrial functional impairment, mitochondrial dynamic, and mitophagy disproportion compared with the vehicle-exposed RIR group. The NAC therapy considerably attenuated the exacerbated effects of BPA, which was associated with increased AMP-activated protein kinase (AMPK), PGC-1α, silent information regulator 3 or sirtuin 3 (SIRT3), and mitofusin 2 (MFN2) expressions but decreased Phosphorylated dynamin-related protein 1 (p-DRP1)/Dynamin-related protein 1 (DRP1), PTEN-induced putative kinase (PINK), and PARKIN expressions. These findings reveal the detrimental effect of repeated BPA exposure on the renal outcomes following the IR episode, and further demonstrate the protective efficacy of NAC by maintaining mitochondrial homeostasis, which is, partly, mediated through the AMPK-PGC-1α-SIRT3 axis.
双酚A（BPA）是一种普遍用于消费品的化学物质，随着人类通过日常消费活动越来越多地接触到它，其暴露已成为全球公共卫生问题。肾缺血再灌注（RIR）是急性肾损伤的主要原因，其患病率高，且多种合并症和死亡率的长期风险增加。由于肾脏易受这些情况影响，我们探讨了RIR发作后的结果是否会受到BPA暴露的影响，并研究了N-乙酰半胱氨酸（NAC）的治疗可能性，包括其涉及的机制。三组雄性Wistar大鼠分别连续五周喂食赋形剂、5和50mg/kg的BPA，然后进行假手术。另外三组接受相同处理的大鼠进行双侧肾缺血再灌注诱导（45分钟缺血，随后24小时再灌注）。另一个RIR组用50mg/kg的BPA加100mg/kg的NAC治疗。与暴露于赋形剂的RIR组相比，经历RIR发作的BPA暴露大鼠表现出RIR损伤的剂量依赖性恶化，表现为肾功能障碍、组织病理学异常、氧化应激、细胞凋亡、线粒体功能损害、线粒体动力学和线粒体自噬失衡加剧。NAC治疗显著减轻了BPA的加剧作用，这与AMP激活蛋白激酶（AMPK）、过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）、沉默信息调节因子3或沉默调节蛋白3（SIRT3）以及线粒体融合蛋白2（MFN2）表达增加有关，但磷酸化动力相关蛋白1（p-DRP1）/动力相关蛋白1（DRP1）、PTEN诱导的假定激酶（PINK）和帕金蛋白表达降低。这些发现揭示了反复BPA暴露对缺血再灌注发作后肾脏结果的有害影响，并进一步证明了NAC通过维持线粒体稳态的保护作用，这部分是通过AMPK-PGC-1α-SIRT3轴介导的。
