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

作　　者：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 

机构地区：[1]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Key Laboratory of Molecular Cardiovascular Science,Ministry of Education,Peking University,100191 Beijing,P.R.China [2]Department of Nephrology,Peking University First Hospital,100034 Beijing,P.R.China [3]Department of Rheumatology and Immunology,Peking University People’s Hospital,Beijing,China [4]Department of Laboratory Medicine,Peking University Third Hospital,100083 Beijing,P.R.China [5]Department of Nephrology,Peking University Third Hospital,100083 Beijing,P.R.China

出　　处：《Signal Transduction and Targeted Therapy》2023年第4期1926-1941,共16页信号转导与靶向治疗（英文）

基　　金：the National Natural Science Foundation of China(No.31872787,82070462,81921001,91939105,and 82170476);the Natural Science Foundation of Beijing Municipality,China(No.M21008).

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 HHcytreated 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.

关 键 词：HYPERTENSIVE glomerular PEROXIDATION 

分 类 号：R692[医药卫生—泌尿科学]