title: Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis-induced arteriovenous fistula failure in chronic kidney disease.
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.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chien
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Fan
authors.forename: Shao-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Chang-Chih
authors.initials: CC
authors.lastname: Kuo
authors.forename: Chih-Hui
authors.initials: CH
authors.lastname: Yang
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Yu
authors.forename: Shih-Pin
authors.initials: SP
authors.lastname: Lee
authors.forename: Dai-Yu
authors.initials: DY
authors.lastname: Cheng
authors.affiliation: Ping-Chia Li, PhD, Department of Occupational Therapy, I-Shou University (Yanchao Campus), No. 8, Yida Rd, Yancho District, Kaohsiung City 824, Taiwan, R.O.C., Tel.: +886 7 6151100 7513, Fax: +886 7 6155150, E-mail: pingchiali@gmail.com; pingchia@isu.edu.tw.
authors.forename: Ping-Chia
authors.initials: PC
authors.lastname: Li
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D017536:Carotid Artery, Common / Q000473:pathology / Q000601:surgery; D002448:Cell Adhesion / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007601:Jugular Veins / Q000473:pathology / Q000601:surgery; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000628:therapy*; D013928:Thromboxane A2 / Q000633:toxicity; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D020246:Venous Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D013928:Thromboxane A2; D000077270:Exenatide; D006861:Hydrogen Peroxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Apoptosis; free radicals; glucagon-like peptide-1; peripheral vascular disease; thrombosis