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 (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.

高同型半胱氨酸血症 (HHcy) 是影响约 85% CKD 患者的慢性肾脏疾病 (CKD) 的危险因素。HHcy刺激B细胞分泌病理性抗体，但该通路是否介导肾损伤尚不清楚。在 HHcy 处理的 2 肾、1 夹 (2K1C) 高血压小鼠模型中，HHcy 激活的 B 细胞分泌抗 β2 糖蛋白 I（_β2GPI) 抗体沉积在肾小球内皮细胞 (GEC) 中，加剧肾小球硬化并降低肾功能。从机制上讲，HHcy 2K1C 小鼠增加了肾脏组织中的磷脂酰乙醇胺 (PE)（18:0/20:4、18:0/22:6、16:0/20:4），这由脂质组学确定。GECs 氧化脂质组学验证了氧化磷脂在 Hcy 活化 B 细胞培养基 (Hcy-B CM) 处理后的增加，包括 PE (18:0/20:4 + 3[O]、PE (18:0a/22:4) + 1[O]、PE (18:0/22:4 + 2[O] 和 PE (18:0/22:4 + 3[O])。PE 合酶乙醇胺激酶 2 (etnk2) 和乙醇胺磷酸胞苷酰转移酶2 (pcyt2) 在 HHcy 2K1C 小鼠的肾脏 GEC 中增加，并促进多不饱和 PE 合成，作为脂质过氧化底物。在 HHcy 2K1C 小鼠和 Hcy-B CM 处理的 GEC 中，铁积累诱导的氧化环境以及转铁蛋白受体 (TFR) 升高和 SLC7A11/谷胱甘肽过氧化物酶 4 (GPX4) 下调导致的脂质过氧化物清除不足导致了 GEC 的肾脏铁死亡。在体内，B 细胞的药理学耗竭或铁死亡的抑制减轻了 HHcy 加重的高血压性肾损伤。因此，我们的研究结果揭示了一种新的机制，通过该机制，B 细胞衍生的致病性抗-β₂ HHcy 产生的 GPI IgG 通过诱导 GECs 铁死亡加剧了高血压肾损伤。靶向 B 细胞或铁死亡可能是改善 HHcy 高血压肾病患者脂质过氧化性肾损伤的可行治疗策略。