A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis
Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism rem...
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doaj-a868da4844104990a646d6008059e8ac2021-09-22T14:23:09ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-09-011210.3389/fphys.2021.680544680544A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of FerroptosisXue Li0Xue Li1Yu Zou2Yuan-Yuan Fu3Jia Xing4Kai-Yue Wang5Peng-Zhi Wan6Xiao-Yue Zhai7Xiao-Yue Zhai8Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, ChinaDepartment of Nephrology, Shengjing Hospital of China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, ChinaDepartment of Nephrology, First Affiliated Hospital of China Medical University, Shenyang, ChinaDepartment of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, ChinaInstitute of Nephropathology, China Medical University, Shenyang, ChinaFolic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.https://www.frontiersin.org/articles/10.3389/fphys.2021.680544/fullA-lipoic acidferroptosisp53folic acidrenal damage |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xue Li Xue Li Yu Zou Yuan-Yuan Fu Jia Xing Kai-Yue Wang Peng-Zhi Wan Xiao-Yue Zhai Xiao-Yue Zhai |
spellingShingle |
Xue Li Xue Li Yu Zou Yuan-Yuan Fu Jia Xing Kai-Yue Wang Peng-Zhi Wan Xiao-Yue Zhai Xiao-Yue Zhai A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis Frontiers in Physiology A-lipoic acid ferroptosis p53 folic acid renal damage |
author_facet |
Xue Li Xue Li Yu Zou Yuan-Yuan Fu Jia Xing Kai-Yue Wang Peng-Zhi Wan Xiao-Yue Zhai Xiao-Yue Zhai |
author_sort |
Xue Li |
title |
A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis |
title_short |
A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis |
title_full |
A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis |
title_fullStr |
A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis |
title_full_unstemmed |
A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis |
title_sort |
a-lipoic acid alleviates folic acid-induced renal damage through inhibition of ferroptosis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2021-09-01 |
description |
Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis. |
topic |
A-lipoic acid ferroptosis p53 folic acid renal damage |
url |
https://www.frontiersin.org/articles/10.3389/fphys.2021.680544/full |
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