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

doi:10.1160/th14-03-0258

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(05): 1051-1064
DOI: 10.1160/th14-03-0258

Animal Models

Schattauer GmbH

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

Chiang-Ting Chien

³Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

,

Shih-Chen Fan

¹Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan

,

Shao-Chieh Lin

⁶Department of Surgery, Division of Colorectal Surgery, National Cheng Kung University Hospital, Tainan, Taiwan

⁷Institute of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

,

Chang-Chih Kuo

²Department of Occupational Therapy, Kaoshiung Medical University, Kaohsiung, Taiwan

,

Chih-Hui Yang

⁴Department of Biological Science & Technology, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan

,

Tzu-Ying Yu

¹Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan

,

Shih-Pin Lee

³Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

,

Dai-Yu Cheng

⁵Department of Bioengineering, College of Engineering, Ta-Tung University, Taipei, Taiwan

,

Ping-Chia Li

¹Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan

› Author Affiliations

Abstract

Summary

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.

Keywords

Apoptosis - free radicals - peripheral vascular disease - glucagon-like peptide-1 - thrombosis

Full Text

References

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