Uremic advanced glycation end products and protein-bound solutes induce endothelial dysfunction through suppression of Krüppel-like factor 2

Keith Saum, Begoña Campos, Diego Celdran-Bonafonte, Lalitha Nayak, Panjamaporn Sangwung, Charuhas Thakar, Prabir Roy-Chaudhury, A. Phillip Owens

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 (KLF2), a key regulator of endothelial function and activation. Methods and Results--Using serum from uremic pigs with chronic renal insufficiency, our results show that KLF2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically, KLF2 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 KLF2 is dependent on activation of the receptor for AGE, as measured by small interfering RNA knockdown of the receptor for AGE. Furthermore, KLF2 suppression promotes endothelial dysfunction, because adenoviral overexpression of KLF2 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 (TTP488) is sufficient to prevent KLF2 suppression in vitro. To decipher the mechanism by which uremic AGEs suppress KLF2 expression, we assessed the role of the receptor for AGE in activation of nuclear factor-jB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of IjBα, we show that translocation of p65 to the nucleus is necessary for KLF2 suppression after treatment with uremic AGEs. Conclusions--These data identify KLF2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.

Original languageEnglish (US)
Article numbere007566
JournalJournal of the American Heart Association
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Keywords

  • Advanced glycosylation end products
  • Chronic kidney disease
  • Endothelial dysfunction
  • Krüppel-like factor 2
  • Uremia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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