B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis
Abstract Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypert...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-03-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01313-x |
| _version_ | 1797863385752141824 |
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| author | Xing Du Xiaolong Ma Ying Tan Fangyu Shao Chun Li Yang Zhao Yutong Miao Lulu Han Guohui Dang Yuwei Song Dongmin Yang Zhenling Deng Yue Wang Changtao Jiang Wei Kong Juan Feng Xian Wang |
| author_facet | Xing Du Xiaolong Ma Ying Tan Fangyu Shao Chun Li Yang Zhao Yutong Miao Lulu Han Guohui Dang Yuwei Song Dongmin Yang Zhenling Deng Yue Wang Changtao Jiang Wei Kong Juan Feng Xian Wang |
| author_sort | Xing Du |
| collection | DOAJ |
| description | Abstract Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (β2GPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-β2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy. |
| first_indexed | 2024-04-09T22:34:45Z |
| format | Article |
| id | doaj.art-33f2eb6783de44fc85988b4e3b8169d3 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-09T22:34:45Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-33f2eb6783de44fc85988b4e3b8169d32023-03-22T12:30:56ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-03-018111610.1038/s41392-023-01313-xB cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosisXing Du0Xiaolong Ma1Ying Tan2Fangyu Shao3Chun Li4Yang Zhao5Yutong Miao6Lulu Han7Guohui Dang8Yuwei Song9Dongmin Yang10Zhenling Deng11Yue Wang12Changtao Jiang13Wei Kong14Juan Feng15Xian Wang16Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Nephrology, Peking University First HospitalDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Rheumatology and Immunology, Peking University People’s HospitalDepartment of Laboratory Medicine, Peking University Third HospitalDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Nephrology, Peking University Third HospitalDepartment of Nephrology, Peking University Third HospitalDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking UniversityAbstract Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (β2GPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-β2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.https://doi.org/10.1038/s41392-023-01313-x |
| spellingShingle | Xing Du Xiaolong Ma Ying Tan Fangyu Shao Chun Li Yang Zhao Yutong Miao Lulu Han Guohui Dang Yuwei Song Dongmin Yang Zhenling Deng Yue Wang Changtao Jiang Wei Kong Juan Feng Xian Wang B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis Signal Transduction and Targeted Therapy |
| title | B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis |
| title_full | B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis |
| title_fullStr | B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis |
| title_full_unstemmed | B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis |
| title_short | B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis |
| title_sort | b cell derived anti beta 2 glycoprotein i antibody mediates hyperhomocysteinemia aggravated hypertensive glomerular lesions by triggering ferroptosis |
| url | https://doi.org/10.1038/s41392-023-01313-x |
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