Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes
The side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722001549 |
| _version_ | 1811322934229204992 |
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| author | Dong-Hyun Kim Hoon-In Choi Jung Sun Park Chang Seong Kim Eun Hui Bae Seong Kwon Ma Soo Wan Kim |
| author_facet | Dong-Hyun Kim Hoon-In Choi Jung Sun Park Chang Seong Kim Eun Hui Bae Seong Kwon Ma Soo Wan Kim |
| author_sort | Dong-Hyun Kim |
| collection | DOAJ |
| description | The side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although previous studies have examined the regulation of ferroptosis in acute kidney injury (AKI), the regulatory mechanism of ferroptosis has not been elucidated. Here, the ability of activated farnesoid X receptor (FXR) to attenuate cisplatin-induced AKI through the regulation of ferroptosis was examined. FXR deficiency exhibited more ferroptosis responses, such as increase in lipid peroxidation, iron content and heme oxygenase 1 protein, and a decrease in glutathione/glutathione disulfide ratio and glutathione peroxidase 4 levels in HK2 cells and mice. Increased blood urea nitrogen, serum creatinine, and ferroptotic responses in the cisplatin-induced AKI mouse model were mitigated upon treatment with the FXR agonist GW4064 but were exacerbated in FXR knockout mice. RNA sequencing analysis revealed that ferroptosis-associated genes were novel targets of FXR. FXR agonist upregulated the expression of lipid and glutathione metabolism-related genes and downregulated cell death-related genes. Additionally, chromatin immunoprecipitation assays, using mice renal tissues, revealed that agonist-activated FXR could bind to its known target genes (Slc51a, Slc51b, Osgin1, and Mafg) and ferroptosis-related genes (Aifm2, Ggt6, and Gsta4). Furthermore, activated FXR-dependent MAFG, a transcriptional repressor, could bind to Hmox1, Nqo1, and Tf in the renal tissues of FXR agonist-treated mice. These findings indicate that activated FXR regulates the transcription of ferroptosis-related genes and protects against cisplatin-induced AKI. |
| first_indexed | 2024-04-13T13:44:56Z |
| format | Article |
| id | doaj.art-a7e60101b6104e288050b1edfe111c8d |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-13T13:44:56Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-a7e60101b6104e288050b1edfe111c8d2022-12-22T02:44:31ZengElsevierRedox Biology2213-23172022-08-0154102382Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genesDong-Hyun Kim0Hoon-In Choi1Jung Sun Park2Chang Seong Kim3Eun Hui Bae4Seong Kwon Ma5Soo Wan Kim6Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaDepartment of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaDepartment of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaDepartment of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaDepartment of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaDepartment of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaCorresponding author. Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju, 61469, South Korea.; Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South KoreaThe side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although previous studies have examined the regulation of ferroptosis in acute kidney injury (AKI), the regulatory mechanism of ferroptosis has not been elucidated. Here, the ability of activated farnesoid X receptor (FXR) to attenuate cisplatin-induced AKI through the regulation of ferroptosis was examined. FXR deficiency exhibited more ferroptosis responses, such as increase in lipid peroxidation, iron content and heme oxygenase 1 protein, and a decrease in glutathione/glutathione disulfide ratio and glutathione peroxidase 4 levels in HK2 cells and mice. Increased blood urea nitrogen, serum creatinine, and ferroptotic responses in the cisplatin-induced AKI mouse model were mitigated upon treatment with the FXR agonist GW4064 but were exacerbated in FXR knockout mice. RNA sequencing analysis revealed that ferroptosis-associated genes were novel targets of FXR. FXR agonist upregulated the expression of lipid and glutathione metabolism-related genes and downregulated cell death-related genes. Additionally, chromatin immunoprecipitation assays, using mice renal tissues, revealed that agonist-activated FXR could bind to its known target genes (Slc51a, Slc51b, Osgin1, and Mafg) and ferroptosis-related genes (Aifm2, Ggt6, and Gsta4). Furthermore, activated FXR-dependent MAFG, a transcriptional repressor, could bind to Hmox1, Nqo1, and Tf in the renal tissues of FXR agonist-treated mice. These findings indicate that activated FXR regulates the transcription of ferroptosis-related genes and protects against cisplatin-induced AKI.http://www.sciencedirect.com/science/article/pii/S2213231722001549Farnesoid X receptor (FXR)FerroptosisAcute kidney injury (AKI)Reactive oxidative stress (ROS)MAF bZIP transcription factor G (MAFG) |
| spellingShingle | Dong-Hyun Kim Hoon-In Choi Jung Sun Park Chang Seong Kim Eun Hui Bae Seong Kwon Ma Soo Wan Kim Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes Redox Biology Farnesoid X receptor (FXR) Ferroptosis Acute kidney injury (AKI) Reactive oxidative stress (ROS) MAF bZIP transcription factor G (MAFG) |
| title | Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes |
| title_full | Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes |
| title_fullStr | Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes |
| title_full_unstemmed | Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes |
| title_short | Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes |
| title_sort | farnesoid x receptor protects against cisplatin induced acute kidney injury by regulating the transcription of ferroptosis related genes |
| topic | Farnesoid X receptor (FXR) Ferroptosis Acute kidney injury (AKI) Reactive oxidative stress (ROS) MAF bZIP transcription factor G (MAFG) |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722001549 |
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