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

Publication ,  Journal Article
Zhang, L; Wu, J-H; Otto, JC; Gurley, SB; Hauser, ER; Shenoy, SK; Nagi, K; Brian, L; Wertman, V; Mattocks, N; Lawson, JH; Freedman, NJ
Published in: Cardiovasc Res
November 1, 2017

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.

Duke Scholars

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Published In

Cardiovasc Res

DOI

EISSN

1755-3245

Publication Date

November 1, 2017

Volume

113

Issue

13

Start / End Page

1551 / 1559

Location

England

Related Subject Headings

  • Vena Cava, Inferior
  • Vascular Diseases
  • Vascular Cell Adhesion Molecule-1
  • Tumor Necrosis Factor-alpha
  • Transcription Factor RelA
  • Time Factors
  • Signal Transduction
  • Renal Insufficiency, Chronic
  • Phosphorylation
  • Neointima
 

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Zhang, L., Wu, J.-H., Otto, J. C., Gurley, S. B., Hauser, E. R., Shenoy, S. K., … Freedman, N. J. (2017). Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells. Cardiovasc Res, 113(13), 1551–1559. https://doi.org/10.1093/cvr/cvx177
Zhang, Lisheng, Jiao-Hui Wu, James C. Otto, Susan B. Gurley, Elizabeth R. Hauser, Sudha K. Shenoy, Karim Nagi, et al. “Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells.Cardiovasc Res 113, no. 13 (November 1, 2017): 1551–59. https://doi.org/10.1093/cvr/cvx177.
Zhang L, Wu J-H, Otto JC, Gurley SB, Hauser ER, Shenoy SK, et al. Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells. Cardiovasc Res. 2017 Nov 1;113(13):1551–9.
Zhang, Lisheng, et al. “Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells.Cardiovasc Res, vol. 113, no. 13, Nov. 2017, pp. 1551–59. Pubmed, doi:10.1093/cvr/cvx177.
Zhang L, Wu J-H, Otto JC, Gurley SB, Hauser ER, Shenoy SK, Nagi K, Brian L, Wertman V, Mattocks N, Lawson JH, Freedman NJ. Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells. Cardiovasc Res. 2017 Nov 1;113(13):1551–1559.
Journal cover image

Published In

Cardiovasc Res

DOI

EISSN

1755-3245

Publication Date

November 1, 2017

Volume

113

Issue

13

Start / End Page

1551 / 1559

Location

England

Related Subject Headings

  • Vena Cava, Inferior
  • Vascular Diseases
  • Vascular Cell Adhesion Molecule-1
  • Tumor Necrosis Factor-alpha
  • Transcription Factor RelA
  • Time Factors
  • Signal Transduction
  • Renal Insufficiency, Chronic
  • Phosphorylation
  • Neointima