Vascular Protective Effect of Exendin-4 in a Diabetic Rat Model of Aortocaval Fistula

Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone, namely the incretin family, secreted by small intestine under a fine-tune regulation in response to glucose concentration. Beneficial effects of GLP-1 on cardiovascular system have also been reported in humans with type II diabetes and stable coronary artery disease. The protective effect is attributed to suppression of programmed cell death including apoptosis and senescence. Additionally, it has been reported that activation of GLP-1 receptor (GLP-1R) by GLP-1 and its agonist ameliorates oxidative stress-induced vascular endothelial dysfunction. However, the mechanism underlying the pleiotropic effect remains to be elucidated. Diabetes is one of the common causes of end-stage renal disease (ESRD) requiring renal replacement therapy in the developed countries. Hemodialysis is currently the main method of renal replacement therapy for patients with ESRD, which necessitates the placement of an arteriovenous (AV) fistula, an artificial graft or a permanent catheter. As AV fistula is the prime choice for patients requiring hemodialysis, the procedures for creating the AV fistula and treatment of the related complications account for over 20% of hospitalizations for dialysis patients. Very limited studies have reported the effect of arterial blood flow on the function and patency of AV fistula, particularly in diabetic patients. Hyperglycemia has been known to increase vascular oxidative stress and causes endothelial dysfunction. There are also extensive data indicating that hyperglycemia enhances release of pro-inflammatory cytokines, which may exacerbate inflammatory reaction in the vasculature of fistula. Most recently, the applicants demonstrated that vascular function and blood flow rate were significantly impaired in the experimental arteriovenous (AV) fistula of rats with streptozotocin-induced diabetes. The reduced blood flow and impaired endothelium-dependent relaxation response of AV fistula in diabetic rats was derived from enhanced activity of pro-inflammatory genes and generation of superoxide anions in the remodeled vasculature. In addition, the numbers of circulating endothelial progenitor cells (EPCs) in the peripheral blood were decreased in rats with hyperglycemia, indicating that the mobilization of EPCs contributing to vasculogenesis is impaired in diabetes. Administration of rosuvastatin, a HMG CoA inhibitor potentiated the vascular endothelial function and blood flow in the AV fistula of diabetic rats by suppression the generation of superoxide anions and increased numbers of circulating EPCs. On the other hand, the preliminary results of our study group showed that treatment with exendin-4 (a GLP-1 analogue) in cultured human umbilical vein endothelial cells (HUVECs) improved the cell viability following exposure to H2O2 in a concentration-dependent fashion. To the knowledge of the applicants, there is currently no previous studies reported the application of GLP-1 analogues in the protection of vascular endothelial function and mobilization of EPCs in maturation of AV fistula of subjects with diabetes. Logistically extended from these preliminary findings, the applicants hypothesize that Exendin-4 attenuates oxidative damage of vascular endothelial cells and mediates vascular protective effect in function AV fistula of animals with diabetes. Administration of GLP-1 analogue may also increase the mobilization of EPCs in the peripheral circulation, and may thus enhance pro-angiogenesis in subjects with hyperglycemia.