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

Abstract

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.

Ginsenoside Rk3 Regulates Tryptophan Metabolism along the Brain–Gut Axis by Targeting Tryptophan Hydroxylase and Remodeling the Intestinal Microenvironment to Alleviate Depressive-Like Behavior in Mice

“…38 Oxidative stress is a critical factor in promoting apoptosis in nervous system diseases. 39 Peripheral 3-HK can cross the BBB and induce oxidative damage by producing ROS after interacting with xanthine oxidase. Furthermore, 3-HK is metabolized to Quin in neuroimmune cells.…”

“…However, disrupting this balance can prompt excessive cell death and immune diseases . Oxidative stress is a critical factor in promoting apoptosis in nervous system diseases . Peripheral 3-HK can cross the BBB and induce oxidative damage by producing ROS after interacting with xanthine oxidase.…”

“…39 Peripheral 3-HK can cross the BBB and induce oxidative damage by producing ROS after interacting with xanthine…”

Role of β2‐glycoprotein I in the pathogenesis of the antiphospholipid syndrome

“…Meanwhile, glomerular endothelium cell injury may be related to vasculitis, inflammation, and vascular sclerosis 66 . We found that HHcy induced the secretion of anti‐β2GPI antibodies by B cells and the deposition of pathogenic antibodies within glomerular endothelial cells, ultimately reducing renal function 67 . It has also been reported that renal endothelial cell dysfunction leads to a decrease in the levels of endodermal vasodilators and an increase in those of vasoconstrictor mediators, thereby increasing vasoconstriction and promoting hypoxia, inflammation, and fibrosis 66 …”

“…66 We found that HHcy induced the secretion of anti-β2GPI antibodies by B cells and the deposition of pathogenic antibodies within glomerular endothelial cells, ultimately reducing renal function. 67 It has also been reported that renal endothelial cell dysfunction leads to a decrease in the levels of endodermal vasodilators and an increase in those of vasoconstrictor mediators, thereby increasing vasoconstriction and promoting hypoxia, inflammation, and fibrosis. 66 The binding of anti-β2GPI antibodies to β2GPI activates endothelial cells to release microparticles/extracellular vesicles, which further stimulate surrounding resting cells with procoagulant and proinflammatory properties in a paracrine/autocrine manner.…”