Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid
Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid
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DOI：
10.1016/j.freeradbiomed.2018.11.005
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发表时间：
2019-01-01
影响因子：
7.4
通讯作者：
Pedraza-Chaverri, Jose
中科院分区：
文献类型：
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作者：
Emiliano Aparicio-Trejo, Omar;Maria Reyes-Fermin, Laura;Pedraza-Chaverri, Jose
叶酸(FA)诱导的急性肾损伤(AKI)是一种广泛用于研究肾脏损伤及其向慢性进展的模型。然而，FA诱导AKI的分子机制仍然知之甚少。由于肾功能依赖于线粒体的动态平衡，已有研究表明线粒体的改变有助于AKI的发展。此外，N-乙酰半胱氨酸(NAC)可以作为保护剂防止线粒体和肾功能障碍，因为它能够增加线粒体谷胱甘肽(GSH)和控制S谷胱甘肽水平，这是一种可逆的翻译后修饰，已成为连接线粒体能量代谢和氧化还原稳态的机制。然而，这一假设还没有被探索过。本研究首次证明，在24小时，FA诱导线粒体生物能、氧化还原状态、动力学和吞线体改变，这些改变参与了AKI的发生机制。另一方面，NAC预先给药能够防止线粒体生物能、氧化还原状态和动力学改变以及肾脏损伤。NAC对线粒体和肾功能的保护作用可能与其保护线粒体的S-谷胱甘肽过程和谷胱甘肽水平有关。综上所述，我们的结果支持在FA诱导的AKI模型中，这些线粒体过程可以作为预防肾损伤及其进展的靶点。
Folic acid (FA)-induced acute kidney injury (AKI) is a widely used model for studies of the renal damage and its progression to chronic state. However, the molecular mechanisms by which FA induces AKI remain poorly understood. Since renal function depends on mitochondrial homeostasis, it has been suggested that mitochondrial alterations contribute to AKI development. Additionally, N-acetyl-cysteine (NAC) can be a protective agent to prevent mitochondrial and renal dysfunction in this model, given its ability to increase mitochondrial glutathione (GSH) and to control the S-glutathionylation levels, a reversible post-translational modification that has emerged as a mechanism able to link mitochondrial energy metabolism and redox homeostasis. However, this hypothesis has not been explored. The present study demonstrates for the first time that, at 24 h, FA induced mitochondrial bioenergetics, redox state, dynamics and mitophagy alterations, which are involved in the mechanisms responsible for the AKI development. On the other hand, NAC preadministration was able to prevent mitochondrial bioenergetics, redox state and dynamics alterations as well as renal damage. The protective effects of NAC on mitochondria and renal function could be related to its observed capacity to preserve the S-glutathionylation process and GSH levels in mitochondria. Taken together, our results support the idea that these mitochondrial processes can be targets for the prevention of the renal damage and its progression in FA-induced AKI model.