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Background  Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease. The accumulation of uremic solutes in this patient population is associated with endothelial dysfunction and accelerated cardiovascular disease. In this study, we examined the impact of the uremic milieu on the endothelial transcription factor, Krüppel‐like factor 2 ( KLF 2), a key regulator of endothelial function and activation.    Methods and Results  Using serum from uremic pigs with chronic renal insufficiency, our results show that  KLF 2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically,  KLF 2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine‐modified albumin, an advanced glycation end product ( AGE ) known to induce endothelial dysfunction.  AGE ‐mediated suppression of  KLF 2 is dependent on activation of the receptor for  AGE , as measured by small interfering  RNA  knockdown of the receptor for  AGE . Furthermore,  KLF 2 suppression promotes endothelial dysfunction, because adenoviral overexpression of  KLF 2 inhibits reactive oxygen species production and leukocyte adhesion in human umbilical vein endothelial cells. In addition, the application of hemodynamic shear stress, prolonged serum dialysis, or treatment with the receptor for  AGE  antagonist azeliragon ( TTP 488) is sufficient to prevent  KLF 2 suppression in vitro. To decipher the mechanism by which uremic  AGE s suppress  KLF 2 expression, we assessed the role of the receptor for  AGE  in activation of nuclear factor‐κB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of IκBα, we show that translocation of p65 to the nucleus is necessary for  KLF 2 suppression after treatment with uremic  AGE s.    Conclusions  These data identify  KLF 2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.

Uremic Advanced Glycation End Products and Protein‐Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel‐Like Factor 2