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

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.