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Abstract: FR-PO186

Endothelial Dysfunction in ESRD Results from Advanced Glycation End-Products (AGE)-Mediated Suppression of Krüppel-Like Factor 2

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction


  • Saum, Keith Louis, University of Cincinnati, Cincinnati, Ohio, United States
  • Campos, Begoña, University of Cincinnati, Cincinnati, Ohio, United States
  • Celdran-Bonafonte, Diego, University of Arizona / BIO 5 Institute, Tucson, Arizona, United States
  • Owens, Albert Phillip, University of Cincinnati, Cincinnati, Ohio, United States
  • Roy-Chaudhury, Prabir, University of Arizona, Tucson, Arizona, United States

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease. The accumulation of uremic toxins in this patient population is associated with endothelial dysfunction and accelerated arteriosclerosis. We investigated the impact of protein-bound uremic toxins such as advanced glycation end products (AGEs) on the expression of Krüppel-like Factor 2 (KLF2), the key regulator of endothelial function and activation.


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 (HUVEC) were treated with increasing concentrations of uremic or non-uremic porcine serum and analyzed for cell viability, apoptosis, and 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. Finally, we investigated nuclear factor kappa-B (NF-KB) signaling as a mechanism underlying the AGE-mediated suppression of KLF2 and the potential of a RAGE antagonist, TTP488, to increase endothelial KLF2 expression and function.


Treatment with uremic serum decreased HUVEC viability and increased apoptosis in a dose-dependent manner compared to non-uremic serum. Furthermore, uremic serum suppressed HUVEC KLF2 expression > 50%, which was reversed by dialysis and shear stress. Of the uremic toxins tested, carboxymethyl-lysine (CML) modified albumin, an AGE, resulted in the greatest suppression of KLF2 similar to uremic serum. Overexpression of KLF2 inhibited the production of ROS and leukocyte adhesion by uremic serum and CML. Inhibition of RAGE-mediated NF-KB signaling blocked the translocation of p65 to the nucleus and suppression of KLF2 by CML.


Suppression of KLF2 by uremic toxins such as AGEs is associated with increased endothelial dysfunction. This study, therefore, identifies suppression of KLF2 as a potential mechanism by which uremic toxins impair endothelial function in regions prone to arteriosclerosis. Future studies targeting this pathway could lead to novel therapies to decrease cardiovascular mortality in ESRD.


  • NIDDK Support