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Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression
Keith Saum1,2, Begoña Campos2, Diego Celdran-Bonafonte3
1University of Cincinnati Medical Scientist Training Program, The University of Cincinnati College of Medicine, Cincinnati, OH.
Insights
Uremic solutes suppress Krüppel-like factor 2 (KLF2) in kidney disease patients, worsening endothelial dysfunction and cardiovascular risk. Restoring KLF2 may protect against these complications.
Area of Science:
- Cardiovascular Science
- Nephrology
- Endothelial Biology
Background:
- Cardiovascular disease is a major complication in end-stage renal disease (ESRD) patients.
- Uremic solutes contribute to endothelial dysfunction and accelerated atherosclerosis in ESRD.
- Krüppel-like factor 2 (KLF2) is a critical regulator of endothelial function.
Purpose of the Study:
- To investigate the impact of the uremic environment on KLF2 expression in endothelial cells.
- To determine the role of KLF2 suppression in uremic endothelial dysfunction.
Main Methods:
- Utilized serum from uremic pigs and in vitro cell models (human umbilical vein endothelial cells).
- Assessed KLF2 expression following treatment with uremic serum, advanced glycation end products (AGEs), and specific signaling pathway modulators.
- Investigated the role of the receptor for AGE (RAGE) and nuclear factor-κB (NF-κB) signaling.
Main Results:
- Uremic milieu and specific solutes like carboxymethyllysine-modified albumin suppressed KLF2 expression.
- AGE-mediated KLF2 suppression was dependent on RAGE activation.
- Overexpression of KLF2 ameliorated endothelial dysfunction markers (ROS production, leukocyte adhesion).
- Hemodynamic shear stress, dialysis, and RAGE antagonist azeliragon prevented KLF2 suppression.
- NF-κB signaling, specifically p65 nuclear translocation, was essential for KLF2 suppression by uremic AGEs.
Conclusions:
- KLF2 suppression is a direct consequence of the uremic milieu.
- This suppression contributes to endothelial dysfunction and cardiovascular disease progression in ESRD.
- Targeting KLF2 or RAGE may offer therapeutic strategies for uremic cardiovascular complications.
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-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 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.
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