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

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.

Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

“…Bax/Bcl-2 ratios, caspase 3 expression, and PARP expression were significantly (Po 0.05) and time-dependently upregulated in rats treated with DM, CAO6h, CAO12h, DM+CAO6h, or DM +CAO12h compared with control rats ( Figure 7E; F [11,35] ICAM-1 expression was significantly and time-dependently upregulated in rats treated with DM (P = 0.037), CAO6h (P = 0.028), CAO12h (P = 0.019), DM+CAO6h (P = 0.011), or DM +CAO12h (P = 0.012) compared with control rats (Figure 7F; F [11,35] = 16.71, P o 0.0001). PEx-4 depressed ICAM-1 expression more effectively (P o0.05) than Ex-4 in CAO and DM +CAO rats.…”

“…Effect of PEx-4 on DM and CAO-Induced Changes in Protein Levels p-Akt expression was significantly and time-dependently downregulated in rats treated with DM (P = 0.011), after CAO 6 hours (CAO6h, P = 0.014), after CAO 12 hours (CAO12h, P = 0.023), after CAO 6 hours in DM (DM+CAO6h, P = 0.017), or after CAO 12 hours in DM (DM+CAO12h, P = 0.005) compared with control rats ( Figure 7B; F [11,35] = 8.75, P o 0.001). PEx-4 restored p-Akt expression more effectively (P o 0.05) than Ex-4 in CAO and DM +CAO rats.…”

“…11 Briefly, the total proteins were homogenized, separated, and transferred onto blocked polyvinylidene fluoride membranes (Millipore Corporation, Bedford, MA, USA , and β-actin (1:1000, Sigma-Aldrich). The signal was visualized on film using a commercial enhanced chemiluminescence kit (Amersham Biosciences, Piscataway, NJ, USA).…”

“…9 GLP-1, and its analog exendin-4 (Ex-4), confer cardiovascular protection in patients with dilated cardiomyopathy, hypertensive heart failure, myocardial infarction, 10 and thrombosis. 11 GLP-1R is widely located throughout the brain; and GLP-1 and Ex-4 provide neuroprotection against neuronal damage through GLP-1R activation. 12,13 Several neurovascular protective mechanisms are involved in the effects of GLP-1R activation, including activation of phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) protective signaling, 11 protein kinase A-mediated inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity-induced oxidative stress, 14 and inhibition of translocation of the p65 subunit of nuclear factor-κB (NF-κB) and mitochondrial pro-apoptotic Bax.…”

“…11 GLP-1R is widely located throughout the brain; and GLP-1 and Ex-4 provide neuroprotection against neuronal damage through GLP-1R activation. 12,13 Several neurovascular protective mechanisms are involved in the effects of GLP-1R activation, including activation of phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) protective signaling, 11 protein kinase A-mediated inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity-induced oxidative stress, 14 and inhibition of translocation of the p65 subunit of nuclear factor-κB (NF-κB) and mitochondrial pro-apoptotic Bax. 15 Ex-4 attenuates stroke injury in patients with Type 2 diabetes by arresting microglia infiltration, increasing neural stem cell proliferation, and depressing metabolic insults.…”