PMID- 36907919
OWN - NLM
STAT- MEDLINE
DCOM- 20230314
LR  - 20230412
IS  - 2059-3635 (Electronic)
IS  - 2095-9907 (Print)
IS  - 2059-3635 (Linking)
VI  - 8
IP  - 1
DP  - 2023 Mar 13
TI  - B cell-derived anti-beta 2 glycoprotein I antibody mediates 
      hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering 
      ferroptosis.
PG  - 103
LID - 10.1038/s41392-023-01313-x [doi]
LID - 103
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Du, Xing
AU  - Du X
AD  - 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.
FAU - Ma, Xiaolong
AU  - Ma X
AD  - 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.
FAU - Tan, Ying
AU  - Tan Y
AD  - Department of Nephrology, Peking University First Hospital, 100034, Beijing, P. 
      R. China.
FAU - Shao, Fangyu
AU  - Shao F
AD  - 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.
FAU - Li, Chun
AU  - Li C
AD  - Department of Rheumatology and Immunology, Peking University People's Hospital, 
      Beijing, China.
FAU - Zhao, Yang
AU  - Zhao Y
AD  - Department of Laboratory Medicine, Peking University Third Hospital, 100083, 
      Beijing, P. R. China.
FAU - Miao, Yutong
AU  - Miao Y
AD  - 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.
FAU - Han, Lulu
AU  - Han L
AD  - 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.
FAU - Dang, Guohui
AU  - Dang G
AD  - 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.
FAU - Song, Yuwei
AU  - Song Y
AD  - 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.
FAU - Yang, Dongmin
AU  - Yang D
AD  - 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.
FAU - Deng, Zhenling
AU  - Deng Z
AD  - Department of Nephrology, Peking University Third Hospital, 100083, Beijing, P. 
      R. China.
FAU - Wang, Yue
AU  - Wang Y
AD  - Department of Nephrology, Peking University Third Hospital, 100083, Beijing, P. 
      R. China.
FAU - Jiang, Changtao
AU  - Jiang C
AD  - 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.
FAU - Kong, Wei
AU  - Kong W
AUID- ORCID: 0000-0001-6720-6810
AD  - 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.
FAU - Feng, Juan
AU  - Feng J
AD  - 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. juanfeng@bjmu.edu.cn.
FAU - Wang, Xian
AU  - Wang X
AD  - 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. xwang@bjmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230313
PL  - England
TA  - Signal Transduct Target Ther
JT  - Signal transduction and targeted therapy
JID - 101676423
RN  - 0 (Glycoproteins)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Ferroptosis
MH  - *Hyperhomocysteinemia/drug therapy/metabolism
MH  - Endothelial Cells/metabolism
MH  - *Kidney Diseases/metabolism
MH  - Glycoproteins
PMC - PMC10008839
COIS- The authors declare no competing interests.
EDAT- 2023/03/14 06:00
MHDA- 2023/03/15 06:00
PMCR- 2023/03/13
CRDT- 2023/03/13 00:17
PHST- 2022/05/31 00:00 [received]
PHST- 2023/01/09 00:00 [accepted]
PHST- 2022/10/14 00:00 [revised]
PHST- 2023/03/13 00:17 [entrez]
PHST- 2023/03/14 06:00 [pubmed]
PHST- 2023/03/15 06:00 [medline]
PHST- 2023/03/13 00:00 [pmc-release]
AID - 10.1038/s41392-023-01313-x [pii]
AID - 1313 [pii]
AID - 10.1038/s41392-023-01313-x [doi]
PST - epublish
SO  - Signal Transduct Target Ther. 2023 Mar 13;8(1):103. doi: 
      10.1038/s41392-023-01313-x.