Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy
Abstract Vascular calcification (VC) is a common complication of chronic kidney disease (CKD), for which no effective therapies are available. Hyperphosphatemia, a feature of CKD, is a well-known inducer of VC. High phosphate (HP)-induced ferroptosis plays a crucial role in CKD-related VC (CKD-VC),...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07260-x |
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| author | Yujia Wang Yuxia Zhang Min Gao Zhiqing Chen Jing Lu Yongqi Li Yan Di Yinan Zhao Bicheng Liu Rining Tang |
| author_facet | Yujia Wang Yuxia Zhang Min Gao Zhiqing Chen Jing Lu Yongqi Li Yan Di Yinan Zhao Bicheng Liu Rining Tang |
| author_sort | Yujia Wang |
| collection | DOAJ |
| description | Abstract Vascular calcification (VC) is a common complication of chronic kidney disease (CKD), for which no effective therapies are available. Hyperphosphatemia, a feature of CKD, is a well-known inducer of VC. High phosphate (HP)-induced ferroptosis plays a crucial role in CKD-related VC (CKD-VC), but the mechanisms remain unclear. Lipocalin-2 (LCN2), an iron-trafficking protein, has been implicated in ferroptosis regulation. In the present study, the role of LCN2 as a potential mediator of CKD-VC was investigated. HP-induced LCN2 expression in the arteries of CKD-VC patients, animal models and vascular smooth muscle cells (VSMCs). LCN2 knockout (LCN2KO) mice and wild-type (WT) mice fed with a high adenine and phosphate (AP) diet were studied to explore CKD-VC. Compared with WT mice, LCN2KO mice showed an amelioration of the CKD-VC induced by the AP diet. The inhibition of LCN2 also alleviated HP-induced calcium deposition and phenotypic transition in VSMCs. Conversely, VSMCs-targeted LCN2 overexpression or recombinant LCN2 treatment exacerbated CKD-VC in vivo and in vitro. Mechanistically, nuclear receptor coactivator 4 (NCOA4)/ferritin heavy chain 1 (FTH1)-mediated ferritinophagy-dependent ferroptosis was involved in LCN2-mediated CKD-VC. Under HP conditions, LCN2 interacted with NCOA4, potentially accelerating the degradation of FTH1 and inducing ferroptosis. The inhibition of LCN2 may rescue the degradation of FTH1 and thus ameliorate ferroptosis, significantly suppressing VSMCs calcification. In summary, our study revealed a novel role for LCN2 induced ferritinophagy-dependent ferroptosis in CKD-VC, and targeting LCN2 might be a promising treatment for CKD-VC. |
| format | Article |
| id | doaj-art-6f90fb6ad7da44d7a6f882fbd95ff9de |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-6f90fb6ad7da44d7a6f882fbd95ff9de2024-12-01T12:47:26ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111810.1038/s41419-024-07260-xLipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagyYujia Wang0Yuxia Zhang1Min Gao2Zhiqing Chen3Jing Lu4Yongqi Li5Yan Di6Yinan Zhao7Bicheng Liu8Rining Tang9Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityInstitute of Nephrology, Zhongda Hospital, School of Medicine, Southeast UniversityAbstract Vascular calcification (VC) is a common complication of chronic kidney disease (CKD), for which no effective therapies are available. Hyperphosphatemia, a feature of CKD, is a well-known inducer of VC. High phosphate (HP)-induced ferroptosis plays a crucial role in CKD-related VC (CKD-VC), but the mechanisms remain unclear. Lipocalin-2 (LCN2), an iron-trafficking protein, has been implicated in ferroptosis regulation. In the present study, the role of LCN2 as a potential mediator of CKD-VC was investigated. HP-induced LCN2 expression in the arteries of CKD-VC patients, animal models and vascular smooth muscle cells (VSMCs). LCN2 knockout (LCN2KO) mice and wild-type (WT) mice fed with a high adenine and phosphate (AP) diet were studied to explore CKD-VC. Compared with WT mice, LCN2KO mice showed an amelioration of the CKD-VC induced by the AP diet. The inhibition of LCN2 also alleviated HP-induced calcium deposition and phenotypic transition in VSMCs. Conversely, VSMCs-targeted LCN2 overexpression or recombinant LCN2 treatment exacerbated CKD-VC in vivo and in vitro. Mechanistically, nuclear receptor coactivator 4 (NCOA4)/ferritin heavy chain 1 (FTH1)-mediated ferritinophagy-dependent ferroptosis was involved in LCN2-mediated CKD-VC. Under HP conditions, LCN2 interacted with NCOA4, potentially accelerating the degradation of FTH1 and inducing ferroptosis. The inhibition of LCN2 may rescue the degradation of FTH1 and thus ameliorate ferroptosis, significantly suppressing VSMCs calcification. In summary, our study revealed a novel role for LCN2 induced ferritinophagy-dependent ferroptosis in CKD-VC, and targeting LCN2 might be a promising treatment for CKD-VC.https://doi.org/10.1038/s41419-024-07260-x |
| spellingShingle | Yujia Wang Yuxia Zhang Min Gao Zhiqing Chen Jing Lu Yongqi Li Yan Di Yinan Zhao Bicheng Liu Rining Tang Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy Cell Death and Disease |
| title | Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy |
| title_full | Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy |
| title_fullStr | Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy |
| title_full_unstemmed | Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy |
| title_short | Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy |
| title_sort | lipocalin 2 promotes ckd vascular calcification by aggravating vsmcs ferroptosis through ncoa4 fth1 mediated ferritinophagy |
| url | https://doi.org/10.1038/s41419-024-07260-x |
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