Roles of Histone Deacetylases in Arteriovenous Fistula Failure Under Disturbed Flow

Chronic kidney disease, which affects 11.9% of adults and its prevalence of the end-stage renal disease (ESRD) is highest in Asia, is a major health problem in the world. More than 90% of the ESRD patients receive hemodialysis, with the creation of hemodialysis vascular access (HVA), including arteriovenous fistula (AVF). Although AVF is the preferred form of permanent hemodialysis access, it still remains significant problems, such as thrombosis, stenosis and vascular access infections. AVF operation has been shown to change hemodynamic environments. However, the relationship between hemodynamic factors and AVF failure remains unclear. By using Doppler ultrasound to detect the flow patterns in human patients with AVF and rat AVF models, we found that flow disturbance with high and oscillatory shear stress (HOSS, ∼30±100 dynes/cm²) is generated in the anastomotic site of AVF. Venous endothelial cells (ECs) in regions of anastomosis showed higher expression of class I histone deacetylases (HDAC-1/2/3) and lower expression of thrombomodulin (TM) in both human patients and rat AVF models in comparison to control subjects. We further developed in vitro flow system to generate HOSS at 30±100 dyne/cm² and laminar shear stress (LSS) at 5 dyne/cm² to mimic flow patterns in the pathophysiological and physiological flow environments of human AVF, respectively. Application of HOSS to venous ECs induces the association of HDAC-3 with krüppel-like factor 2 (KLF2) to deacetylate KLF2, resulting in the down-regulation of TM. Intraperitoneal administration of valproic acid (VPA), which is a specific inhibitor of class I HDACs, into AVF rats inhibits the increased formation of stenosis at anastomotic sites. Our findings demonstrate that flow disturbance with HOSS can induce HDAC-3 to deacetylate KLF2 and repress TM, and hence contribute to AVF stenosis and failure. Such information may help to generate new approaches for therapeutic interventions against inflammation and thrombosis in AVF in patients.