Abstract: SA-PO983
Endothelial-Specific Krüppel-Like Factor 2 Inactivation Promotes Endothelial Dysfunction in the Setting of Uremia
Session Information
- Hypertension and CVD: Mechanisms - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Saum, Keith Louis, University of Cincinnati, Cincinnati, Ohio, United States
- Campos, Begoña, University of Cincinnati, Cincinnati, Ohio, United States
- Jarrouj, Aous, Banner-University of Arizona, Tucson, Arizona, United States
- Celdran-Bonafonte, Diego, University of Arizona / BIO 5 Institute, Tucson, Arizona, United States
- Roy-Chaudhury, Prabir, University of Arizona, Tucson, Arizona, United States
- Owens, Albert Phillip, University of Cincinnati, Cincinnati, Ohio, United States
Background
Uremic solutes that accumulate in end-stage renal disease(ESRD) may contribute to endothelial dysfunction and subsequent cardiovascular disease and vascular access dysfunction in ESRD patients. However, the mechanisms which mediate uremia-induced endothelial dysfunction in ESRD are not understood. Kruppel-like factors(KLFs) are key regulators of endothelial homeostasis which may be affected by the uremic milieu. In this study we examined the role of endothelial KLF2 in mediating endothelial dysfunction in the setting of uremia
Methods
We used serum from a porcine model of chronic renal failure to assess the impact of uremia on endothelial KLF2 expression in vitro. Human umbilical vein endothelial cells (HUVECs) were treated with increasing concentrations of uremic or non-uremic porcine serum and analyzed for KLF2 expression. Similarly, cells were treated with individual protein-bound toxins at average uremic concentrations. Reactive oxygen species (ROS) production and monocyte adhesion were then assessed in treated cells with and without KLF2 overexpression. To assess if the loss of KLF2 impairs endothelial function in vivo, we quantified flow-mediated dilation (FMD) of the femoral artery in endothelial-specific KLF2 conditional knockout (cKO) mice after 5 minutes of hindlimb ischemia
Results
KLF2 expression was dose-dependently decreased in HUVECs with uremic serum versus normal serum. Carboxymethyl-lysine(CML) modified albumin, a uremic advanced glycation end-product(AGE), also inhibited KLF2 expression. KLF2 suppression also promoted endothelial dysfunction in vitro, as adenoviral overexpression of KLF2 inhibited reactive oxygen species production and leukocyte adhesion in HUVECs treated with uremic serum or CML-AGE. Assessment of FMD in KLF2cKO mice demonstrated a 50%reduction in vasodilation compared to controls. The lack of femoral artery vasodilation in KLF2cKO mice was also accompanied by an attenuated return of wall shear stress to baseline independent of blood velocity
Conclusion
Collectively, these observations implicate loss of endothelial KLF2 as a mediator of endothelial dysfunction in the setting of uremia, and suggest that elevating KLF2 expression may be a novel strategy for prevention and treatment of vascular access dysfunction and cardiovascular disease in ESRD