TitleB cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis
AuthorsDu, Xing
Ma, Xiaolong
Tan, Ying
Shao, Fangyu
Li, Chun
Zhao, Yang
Miao, Yutong
Han, Lulu
Dang, Guohui
Song, Yuwei
Yang, Dongmin
Deng, Zhenling
Wang, Yue
Jiang, Changtao
Kong, Wei
Feng, Juan
Wang, Xian
AffiliationPeking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing 100191, Peoples R China
Peking Univ First Hosp, Dept Nephrol, Beijing 100034, Peoples R China
Peking Univ Peoples Hosp, Dept Rheumatol & Immunol, Beijing, Peoples R China
Peking Univ Third Hosp, Dept Lab Med, Beijing 100083, Peoples R China
Peking Univ Third Hosp, Dept Nephrol, Beijing 100083, Peoples R China
KeywordsCHRONIC KIDNEY-DISEASE
ANTIPHOSPHOLIPID SYNDROME
ENDOTHELIAL-CELLS
HOMOCYSTEINE
PATHWAY
PEROXIDATION
CONTRIBUTES
LYMPHOCYTES
SENSITIVITY
ACTIVATION
Issue Date13-Mar-2023
PublisherSIGNAL TRANSDUCTION AND TARGETED THERAPY
AbstractHyperhomocysteinemia (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 (beta(2)GPI) 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-beta(2)GPI 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.
URIhttp://hdl.handle.net/20.500.11897/673054
ISSN2095-9907
DOI10.1038/s41392-023-01313-x
IndexedSCI(E)
Appears in Collections:基础医学院
第一医院
人民医院
第三医院

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