B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis

被引：28

作者：

Du, Xing ^{[1
]}

Ma, Xiaolong ^{[1
]}

Tan, Ying ^{[2
]}

Shao, Fangyu ^{[1
]}

Li, Chun ^{[3
]}

Zhao, Yang ^{[4
]}

Miao, Yutong ^{[1
]}

Han, Lulu ^{[1
]}

Dang, Guohui ^{[1
]}

Song, Yuwei ^{[1
]}

Yang, Dongmin ^{[1
]}

Deng, Zhenling ^{[5
]}

Wang, Yue ^{[5
]}

Jiang, Changtao ^{[1
]}

Kong, Wei ^{[1
]}

Feng, Juan ^{[1
]}

Wang, Xian ^{[1
]}

机构：

[1] Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing 100191, Peoples R China

[2] Peking Univ First Hosp, Dept Nephrol, Beijing 100034, Peoples R China

[3] Peking Univ Peoples Hosp, Dept Rheumatol & Immunol, Beijing, Peoples R China

[4] Peking Univ Third Hosp, Dept Lab Med, Beijing 100083, Peoples R China

[5] Peking Univ Third Hosp, Dept Nephrol, Beijing 100083, Peoples R China

来源：

SIGNAL TRANSDUCTION AND TARGETED THERAPY | 2023年 / 8卷 / 01期

基金：

中国国家自然科学基金;

关键词：

CHRONIC KIDNEY-DISEASE; ANTIPHOSPHOLIPID SYNDROME; ENDOTHELIAL-CELLS; HOMOCYSTEINE; PATHWAY; PEROXIDATION; CONTRIBUTES; LYMPHOCYTES; SENSITIVITY; ACTIVATION;

D O I：

10.1038/s41392-023-01313-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (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.

引用

页数：16

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