Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis- induced arteriovenous fistula failure in chronic kidney d isease

Chiang Ting Chien, Shih Chen Fan, Shao-Chieh Lin, Chang Chih Kuo, Chih Hui Yang, Tzu Ying Yu, Shih Pin Lee, Dai Yu Cheng, Ping Chia Li

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

High shear stress that develops in the arteriovenous fistula of chronic kidney diseases (CKD) may increase H2O2 and thromboxane A2 (TXA2) release, thereby exacerbating endothelial dysfunction, thrombosis, and neointimal hyperplasia. We investigated whether glucagon-like peptide-1 receptor agonist/exendin-4, a potentially cardiovascular protective agent, could improve TXA2-induced arteriovenous fistula injury in CKD. TXA2 administration to H2O2-exposed human umbilical vein endothelial cells increased apoptosis, senescence, and detachment; these phenotypes were associated with the downregulation of phosphorylated endothelial nitric oxide synthase/heme oxygenase-1 (eNOS/HO-1) signalling. Exendin-4 reduced H2O2/TXA2-induced endothelial injury via inhibition of apoptosis-related mechanisms and restoration of phosphorylated eNOS/HO-1 signalling. Male Wistar rats subjected to right common carotid artery-external jugular vein anastomosis were treated with exendin-4 via cervical implant osmotic pumps for 16–42 days. High shear stress induced by the arteriovenous fistula significantly increased venous haemodynamics, blood and tissue H2O2 and TXB2 levels, macrophage/monocyte infiltration, fibrosis, proliferation, and adhesion molecule-1 expression. Apoptosis was also increased due to NADPH oxidase gp91 activation and mitochondrial Bax translocation in the proximal end of the jugular vein of CKD rats. Exendin-4-treatment of rats with CKD led to the restoration of normal endothelial morphology and correction of arteriovenous fistula function. Exendin-4 treatment or thromboxane synthase gene deletion in CKD mice markedly reduced ADP-stimulated platelet adhesion to venous endothelium, and prevented venous occlusion in FeCl3-injured vessels by upregulation of HO-1. Together, these data reveal that the use of glucagon-like peptide-1 receptor agonists is an effective strategy for treatment of CKD-induced arteriovenous fistula failure.

Original languageEnglish
Pages (from-to)1051-1064
Number of pages14
JournalThrombosis and Haemostasis
Volume112
Issue number5
DOIs
Publication statusPublished - 2013 Nov 1

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Arteriovenous Fistula
Chronic Renal Insufficiency
Venous Thrombosis
Chronic Kidney Failure
Thromboxane A2
Heme Oxygenase-1
Nitric Oxide Synthase Type III
Jugular Veins
Apoptosis
Protective Agents
Cardiovascular Agents
NADPH Oxidase
Thromboxanes
Common Carotid Artery
Human Umbilical Vein Endothelial Cells
Gene Deletion
Wounds and Injuries
Adenosine Diphosphate
Endothelium
Hyperplasia

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Chien, Chiang Ting ; Fan, Shih Chen ; Lin, Shao-Chieh ; Kuo, Chang Chih ; Yang, Chih Hui ; Yu, Tzu Ying ; Lee, Shih Pin ; Cheng, Dai Yu ; Li, Ping Chia. / Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis- induced arteriovenous fistula failure in chronic kidney d isease. In: Thrombosis and Haemostasis. 2013 ; Vol. 112, No. 5. pp. 1051-1064.
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Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis- induced arteriovenous fistula failure in chronic kidney d isease. / Chien, Chiang Ting; Fan, Shih Chen; Lin, Shao-Chieh; Kuo, Chang Chih; Yang, Chih Hui; Yu, Tzu Ying; Lee, Shih Pin; Cheng, Dai Yu; Li, Ping Chia.

In: Thrombosis and Haemostasis, Vol. 112, No. 5, 01.11.2013, p. 1051-1064.

Research output: Contribution to journalArticle

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