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

Jiyeon Yang1, Pu Fang1, Daohai Yu1

  • 1From 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.).

Circulation Research
|December 20, 2016
PubMed

Insights

Chronic kidney disease (CKD) patients exhibit elevated CD40 monocytes, a novel inflammatory subset linked to cardiovascular disease risk. Hyperhomocysteinemia drives this monocyte differentiation, suggesting CD40 monocytes as a biomarker for CKD severity.

Area of Science:

  • Immunology
  • Nephrology
  • Cardiovascular Medicine

Background:

  • Patients with chronic kidney disease (CKD) often develop hyperhomocysteinemia.
  • Hyperhomocysteinemia is associated with a significantly higher cardiovascular mortality risk in CKD patients.

Purpose of the Study:

  • To investigate monocyte differentiation in patients with chronic kidney disease (CKD) and cardiovascular disease (CVD).
  • To identify novel inflammatory monocyte subsets and their role in CKD and CVD.

Main Methods:

  • Utilized CKD-monocyte mRNA array analysis to identify CD40 as a CKD-related monocyte activation gene.
  • Recruited patients with CVD/CKD and healthy subjects for comparative analysis of monocyte subsets and plasma biomarkers.
  • Employed techniques including flow cytometry, plasma homocysteine level measurements, and analysis of inflammatory cytokine levels (TNF-α, IL-6, IFN-γ).

Main Results:

  • Identified CD40 monocytes (CD40+CD14+) as a potent inflammatory subset, exceeding intermediate monocytes (CD14++CD16+).
  • Observed elevated CD40 monocyte subsets, plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine in CVD and further increased levels in CVD+CKD patients.
  • Demonstrated positive correlations between CD40 monocyte subsets and homocysteine/S-adenosylmethionine/S-adenosylhomocysteine levels, and a negative correlation with estimated glomerular filtration rate (eGFR).
  • Established hyperhomocysteinemia as a mediator for CKD-induced CD40 intermediate monocyte differentiation and reduced S-adenosylmethionine/S-adenosylhomocysteine for CKD-induced CD40/CD40 intermediate monocyte differentiation.
  • Found elevated soluble CD40 ligand (sCD40L), TNF-α, IL-6, and IFN-γ levels in CVD/CKD patients.
  • Showed that CKD serum, homocysteine, sCD40L, and increased inflammatory cytokines induced CD40/CD40 intermediate monocyte differentiation.
  • Confirmed that homocysteine inhibits DNA methyltransferase-1 activity, promoting CD40 intermediate monocyte differentiation, an effect reversed by folic acid.

Conclusions:

  • CD40 monocyte represents a novel inflammatory monocyte subset and a potential biomarker for CKD severity.
  • Hyperhomocysteinemia plays a crucial role in mediating CD40 monocyte differentiation in CKD through sCD40L induction and CD40 DNA hypomethylation.
Abstract

Keywords:
CD40 ligandDNA methylationhomocysteinemonocytesrenal insufficiency, chronic

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