Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells.

Zhang, Lisheng

Wu, Jiao-Hui

Otto, James C

Gurley, Susan B

Hauser, Elizabeth R

Shenoy, Sudha K

Nagi, Karim

Brian, Leigh

Wertman, Virginia

Mattocks, Natalie

Lawson, Jeffrey H

Freedman, Neil J

England

2017-11-08T14:00:36Z

2017-11-08T14:00:36Z

2017-11-01

Aims: Chronic kidney disease (CKD) is a powerful independent risk factor for cardiovascular events, including vein graft failure. Because CKD impairs the clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote vein graft neointimal hyperplasia. Methods and results: We modelled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduced glomerular filtration rate by 60%, and we modelled vein grafting with inferior-vena-cava-to-carotid interposition grafting. CKD increased vein graft neointimal hyperplasia four-fold, decreased vein graft re-endothelialization two-fold, and increased serum levels of interleukin-9 (IL-9) five-fold. By quantitative immunofluorescence and histochemical staining, vein grafts from CKD mice demonstrated a ∼two-fold higher prevalence of mast cells, and a six-fold higher prevalence of activated mast cells. Concordantly, vein grafts from CKD mice showed higher levels of TNF and NFκB activation, as judged by phosphorylation of NFκB p65 on Ser536 and by expression of VCAM-1. Arteriovenous fistula veins from humans with CKD also showed up-regulation of mast cells and IL-9. Treating CKD mice with IL-9-neutralizing IgG reduced vein graft neointimal area four-fold, increased vein graft re-endothelialization ∼two-fold, and reduced vein graft total and activated mast cell levels two- and four-fold, respectively. Treating CKD mice with the mast cell stabilizer cromolyn reduced neointimal hyperplasia and increased re-endothelialization in vein grafts. In vitro, IL-9 promoted endothelial cell apoptosis but had no effect on smooth muscle cell proliferation. Conclusion: CKD aggravates vein graft disease through mechanisms involving IL-9 and mast cell activation.

https://www.ncbi.nlm.nih.gov/pubmed/29048463

4100215

1755-3245

https://hdl.handle.net/10161/15737

eng

Oxford University Press (OUP)

Cardiovasc Res

10.1093/cvr/cvx177

Cytokines

Endothelial cells

Mast cells

Neointimal hyperplasia

Smooth muscle cells

Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells.

Journal article

Hauser, Elizabeth R|0000-0003-0367-9189

Freedman, Neil J|0000-0002-8593-8676

https://www.ncbi.nlm.nih.gov/pubmed/29048463

1551

1559

13

Basic Science Departments

Biostatistics & Bioinformatics

Clinical Science Departments

Duke

Duke Molecular Physiology Institute

Institutes and Centers

Medicine

Medicine, Cardiology

Pathology

School of Medicine

Surgery

Surgery, Vascular Surgery

Published

113