Abstract
Background: Uremic solutes that accumulate in end-stage renal disease (ESRD) contribute to endothelial dysfunction and subsequent cardiovascular disease in ESRD patients. However, the specific mechanisms which mediate uremia-induced endothelial dysfunction in ESRD are not understood. Kruppel-like factors (KLFs) are important regulators of endothelial homeostasis which may be affected by the uremic milieu. In this study, we examined the role and regulation of endothelial KLF2 in mediating endothelial dysfunction in the setting of uremia. Methods and Results: First, we assessed the impact of the uremic milieu on endothelial gene expression utilizing serum from uremic and non-uremic pigs with chronic renal insufficiency. We demonstrate that KLF2 expression was dose-dependently decreased with uremic serum in human umbilical vein endothelial cells (HUVECS) versus normal serum which was reversed by prolonged serum dialysis or the application of laminar shear stress. Carboxymethyl-lysine (CML) modified albumin, a uremic advanced glycation end-product (AGE), also inhibited KLF2 expression. This effect was completely abrogated by receptor for AGE (RAGE) siRNA, as well as by a constitutively active form of IκBα, implicating a role for RAGE activation and the NF-κB signaling pathway. 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. For in vivo translation, we utilized high-frequency ultrasound and quantified flow-mediated dilation of the femoral artery in endothelial-specific KLF2 conditional knockout (cKO) mice after 5 minutes of hindlimb ischemia and demonstrated a 50% reduction in vasodilation in KLF2 cKO mice compared to controls. The lack of femoral artery vasodilation in KLF2 cKO mice was also accompanied by attenuated return of wall shear stress to baseline independent of blood velocity. Conclusions: Collectively, these observations implicate loss of endothelial KLF2 as 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 cardiovascular disease in ESRD.
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