Open AccessUremic Advanced Glycation End Products and Protein‐Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel‐Like Factor 2
Author(s) -
Saum Keith,
Campos Begoña,
CeldranBonafonte Diego,
Nayak Lalitha,
Sangwung Panjamaporn,
Thakar Charuhas,
RoyChaudhury Prabir,
Owens A. Phillip
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.007566
Subject(s) - klf2 , endothelial dysfunction , medicine , umbilical vein , endocrinology , glycation , advanced glycation end product , population , endothelial activation , endothelium , endothelial stem cell , cancer research , receptor , transcription factor , biology , in vitro , biochemistry , environmental health , gene
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.