Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation

Jiyeon Yang; Pu Fang; Daohai Yu; Lixiao Zhang; Daqing Zhang; Xiaohua Jiang; William Y Yang; Teodoro Bottiglieri; Satya P Kunapuli; Jun Yu; Eric T Choi; Yong Ji; Xiaofeng Yang; Hong Wang

doi:10.1161/CIRCRESAHA.116.308750

Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation

Circ Res. 2016 Nov 11;119(11):1226-1241. doi: 10.1161/CIRCRESAHA.116.308750.

Authors

Affiliations

¹ 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.).
² 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.

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.

Keywords: CD40 ligand; DNA methylation; homocysteine; monocytes; renal insufficiency, chronic.

MeSH terms

Biomarkers / blood
CD40 Antigens / blood*
Cardiovascular Diseases / blood
Cardiovascular Diseases / pathology
Cell Differentiation / physiology
Cells, Cultured
DNA Methylation / physiology*
Female
Homocysteine / blood*
Humans
Male
Middle Aged
Monocytes / metabolism*
Monocytes / pathology
Renal Insufficiency, Chronic / blood*
Renal Insufficiency, Chronic / pathology

Substances

Biomarkers
CD40 Antigens
Homocysteine

Abstract

MeSH terms

Substances

Grants and funding