title: Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation.
abstract: BACKGROUND
  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).
  
  
  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.
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Pu
authors.initials: P
authors.lastname: Fang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Lixiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Daqing
authors.initials: D
authors.lastname: Zhang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: William Y
authors.initials: WY
authors.lastname: Yang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.). yongji@njmu.edu.cn hongw@temple.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.).
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Centers for Metabolic Disease Research (J.Y.Y., P.F., L.Z., X.J., W.Y.Y., J.Y., X.Y., H.W.), Cardiovascular Research (J.Y.Y., D.Y., X.Y., H.W.), Department of Clinical Sciences, and Sol Sherry Thrombosis Research (J.Y.Y., S.P.K., X.Y., H.W.), Departments of Pharmacology, Physiology and Surgery (J.Y., E.T.C., H.W.), Temple University School of Medicine, Philadelphia, PA; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (Y.J.); Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Liaoning, P. R. China (D.Z.); and Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX (T.B.). yongji@njmu.edu.cn hongw@temple.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D015415:Biomarkers / Q000097:blood; D019013:CD40 Antigens / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000473:pathology
chemical_list: D015415:Biomarkers; D019013:CD40 Antigens; D006710:Homocysteine
keywords: CD40 ligand; DNA methylation; homocysteine; monocytes; renal insufficiency, chronic