KUO KO-LIN1,2, HUNG SZU-CHUN1, LEE TZONG-SHYUAN2, TARNG DER-CHERNG2,3,4 1Division of Nephrology, Taipei Tzuchi Hospital; 2Department and Institute of Physiology, National Yang-Ming University, Taipei; 3Institute of Clinical Medicine, National Yang-Ming University, Taipei; 4Division of Nephrology, Department

of Medicine and Immunology Research Centre, Taipei Veterans General Hospital, Taipei, Taiwan Introduction: High-dose intravenous (IV) iron supplementation is associated with adverse cardiovascular outcomes in patients with chronic kidney disease (CKD), but the underlying mechanism is unknown. Our study investigated the causative role of iron sucrose in leukocyte-endothelium interactions, an index

of early atherogenesis, and learn more subsequent atherosclerosis in mice with remnant kidney. Methods and Results: We first found Selleckchem EPZ-6438 that expressions of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and adhesion of U937 were increased in iron-treated human aortic endothelial cells through NADPH oxidase (NOx) and nuclear factor-kB (NF-kB) signaling but could be suppressed through co-treatment with siRNA on p22phox subunit of NOx or NF-kB, as well as anti-ICAM-1/-VCAM-1 antibodies. In vivo experiments, sham operations, subtotal nephrectomy in male

C57BL/6 mice or uninephrectomy in male apolipoprotein E–deficient (ApoE−/−) mice were performed and followed by saline or parenteral iron loading. Mononuclear–endothelial adhesion and atherosclerotic lesions of the proximal aorta were measured. Iron sucrose significantly increased tissue superoxide production and expression of tissue cell adhesion molecules, and aggravated endothelial mafosfamide adhesiveness in mice with subtotal nephrectomy. Moreover, iron sucrose exacerbated atherosclerosis in the aorta of ApoE−/− mice with uninephrectomy. In CKD patients, IV iron sucrose increased circulating mononuclear superoxide production and soluble adhesion molecules, and mononuclear–endothelial adhesion as compared with healthy subjects or untreated patients. Conclusion: Iron sucrose aggravated endothelial dysfunction through NOx/NF-kB/CAM signaling, increased mononuclear–endothelial adhesion, and exacerbated atherosclerosis in mice with remnant kidney. Our study proposed a novel causative role for therapeutic iron in cardiovascular complications in CKD patients.