Higher Concentrations of Folic Acid Cause Oxidative Stress, Acute Cytotoxicity, and Long-Term Fibrogenic Changes in Kidney Epithelial Cells.
Higher Concentrations of Folic Acid Cause Oxidative Stress, Acute Cytotoxicity, and Long-Term Fibrogenic Changes in Kidney Epithelial Cells.
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DOI：
10.1021/acs.chemrestox.2c00258
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发表时间：
2022-11-21
影响因子：
4.1
通讯作者：
Singh KP
中科院分区：
文献类型：
--
作者：
Kandel R;Singh KP
肾脏纤维化是慢性肾脏病 (CKD) 的常见步骤，其发病率在全球范围内不断增加。反复急性肾损伤后的异常恢复会导致纤维化。肾脏纤维化变化的机制尚不完全清楚。叶酸诱导的小鼠肾纤维化是研究肾纤维化的体内模型，但其机制尚不清楚。此外，尚未研究较高浓度的叶酸对体外肾上皮细胞的影响。氧化应激是肾毒物的常见特性。因此，本研究利用体外肾近端肾小管上皮细胞培养模型评估叶酸诱导的氧化应激在纤维化变化中的作用。为了获得全面而可靠的数据，使用较高浓度的叶酸短期和长期处理来自人和小鼠肾上皮的三种不同细胞系，并在细胞和分子水平上确定其效果。 MTT 测定的细胞活力结果和 DCF 测定的活性氧 (ROS) 水平测量结果表明，叶酸在急性暴露时会引起细胞毒性并增加 ROS 水平。与抗氧化剂 N-乙酰半胱氨酸 (NAC) 共同处理可保护细胞毒性作用，表明叶酸诱导的氧化应激在细胞毒性中的作用。相比之下，长期接触叶酸会导致生长加快、DNA损伤，以及EMT、纤维化、氧化应激和氧化DNA损伤的标记基因表达的变化。其中一些变化，特别是急性影响，可以通过与抗氧化剂 NAC 共同治疗来消除。总之，本研究的新发现表明，较高浓度的叶酸诱导的氧化应激是肾上皮细胞中细胞毒性（急性效应）和纤维化变化（长期效应）的驱动因素。
Kidney fibrosis is a common step during chronic kidney disease (CKD), and its incidence has been increasing worldwide. Aberrant recovery after repeated acute kidney injury leads to fibrosis. The mechanism of fibrogenic changes in the kidney is not fully understood. Folic acid-induced kidney fibrosis in mice is an established in vivo model to study kidney fibrosis, but the mechanism is poorly understood. Moreover, the effect of higher concentrations of folic acid on kidney epithelial cells in vitro has not yet been studied. Oxidative stress is a common property of nephrotoxicants. Therefore, this study evaluated the role of folic acid-induced oxidative stress in fibrogenic changes by using the in vitro renal proximal tubular epithelial cell culture model. To obtain comprehensive and robust data, three different cell lines derived from human and mouse kidney epithelium were treated with higher concentrations of folic acid for both acute and long-term durations, and the effects were determined at the cellular and molecular levels. The result of cell viability by the MTT assay and the measurement of reactive oxygen species (ROS) levels by the DCF assay revealed that folic acid caused cytotoxicity and increased levels of ROS in acute exposure. The cotreatment with antioxidant N-acetyl cysteine (NAC) protected the cytotoxic effect, suggesting the role of folic acid-induced oxidative stress in cytotoxicity. In contrast, the long-term exposure to folic acid caused increased growth, DNA damage, and changes in the expression of marker genes for EMT, fibrosis, oxidative stress, and oxidative DNA damage. Some of these changes, particularly the acute effects, were abrogated by cotreatment with antioxidant NAC. In summary, the novel findings of this study suggest that higher concentrations of folic acid-induced oxidative stress act as the driver of cytotoxicity as an acute effect and of fibrotic changes as a long-term effect in kidney epithelial cells.
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影响因子：
5.9
作者：
通讯作者：
--
影响因子：
7.4
作者：
Emiliano Aparicio-Trejo, Omar;Maria Reyes-Fermin, Laura;Pedraza-Chaverri, Jose
通讯作者：
Pedraza-Chaverri, Jose
DOI：
10.1073/pnas.81.22.6943
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
GUPTA, RC
通讯作者：
GUPTA, RC
影响因子：
7.1
作者：
Pfeiffer, CM;Caudill, SP;Sampson, EJ
通讯作者：
Sampson, EJ
DOI：
10.1152/ajprenal.00128.2018
发表时间：
2018-11-01
影响因子：
4.2
作者：
Jiang, Kai;Ponzo, Tristan A.;Lerman, Lilach O.
通讯作者：
Lerman, Lilach O.