Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation. Issue 11 (11th November 2016)

• Record Type: Journal Article
• Authors: Yang, Jiyeon; Fang, Pu; Yu, Daohai; Zhang, Lixiao; Zhang, Daqing; Jiang, Xiaohua; Yang, William Y.; Bottiglieri, Teodoro; Kunapuli, Satya P.; Yu, Jun; Choi, Eric T.; Ji, Yong; Yang, Xiaofeng; Wang, Hong
• Is Part Of: Circulation research. Volume 119:Issue 11(2016)
• Publication Date: 2016-11-11
• Subjects: CD40 ligand -- DNA methylation -- homocysteine -- monocytes -- renal insufficiency, chronic; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.308750
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: : Patients with chronic kidney disease (CKD) develop hyperhomocysteinemia and have a higher cardiovascular mortality than those without hyperhomocysteinemia by 10-fold. Objective: : We investigated monocyte differentiation in human CKD and cardiovascular disease (CVD). Methods and Results: : We identified CD40 as a CKD-related monocyte activation gene using CKD-monocyte -mRNA array analysis and classified CD40 monocyte (CD40 + CD14 + ) as a stronger inflammatory subset than the intermediate monocyte (CD14 ++ CD16 + ) subset. We recruited 27 patients with CVD/CKD and 14 healthy subjects and found that CD40/CD40 classical/CD40 intermediate monocyte (CD40 + CD14 + /CD40 + CD14 ++ CD16 – /CD40 + CD14 ++ CD16 + ), plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine levels were higher in CVD and further elevated in CVD+CKD. CD40 and CD40 intermediate subsets were positively correlated with plasma/cellular homocysteine levels, S-adenosylhomocysteine and S-adenosylmethionine but negatively correlated with estimated glomerular filtration rate. Hyperhomocysteinemia was established as a likely mediator for CKD-induced CD40 intermediate monocyte, and reduced S-adenosylhomocysteine/S-adenosylmethionine was established for CKD-induced CD40/CD40 intermediate monocyte. Soluble CD40 ligand, tumor necrosis factor (TNF)-α/interleukin (IL)-6/interferon (IFN)-γ levels were elevated in CVD/CKD. CKD serum/homocysteine/CD40L/increased TNF-α/IL-6/IFN-γ–induced CD40/CD40 intermediate monocyte in peripheral blood monocyte. Homocysteine and CKD serum-induced CD40 monocyte were prevented by neutralizing antibodies against CD40L/TNF-α/IL-6. DNA hypomethylation was found on nuclear factor-κB consensus element in CD40 promoter in white blood cells from patients with CKD with lower S-adenosylmethionine / S-adenosylhomocysteine ratios. Finally, homocysteine inhibited DNA methyltransferase-1 activity and promoted CD40 intermediate monocyte differentiation, which was reversed by folic acid in peripheral blood monocyte. Conclusions: : CD40 monocyte is a novel inflammatory monocyte subset that appears to be a biomarker for CKD severity. Hyperhomocysteinemia mediates CD40 monocyte differentiation via soluble CD40 ligand induction and CD40 DNA hypomethylation in CKD. Abstract : Supplemental Digital Content is available in the text.