Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

Eva Harlacher, Julia Wollenhaupt, Constance C F M J Baaten*, Heidi Noels*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

8 Citations (Web of Science)

Abstract

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

Original languageEnglish
Article number531
Number of pages21
JournalInternational journal of molecular sciences
Volume23
Issue number1
DOIs
Publication statusPublished - 4 Jan 2022

Keywords

  • Animals
  • Apoptosis
  • Biomarkers
  • Cardiovascular Diseases/complications
  • Disease Susceptibility
  • Endoplasmic Reticulum Stress
  • Endothelial Cells/drug effects
  • Endothelium, Vascular/metabolism
  • Humans
  • Nitric Oxide/metabolism
  • Oxidative Stress
  • Protein Processing, Post-Translational
  • Renal Insufficiency, Chronic/diagnosis
  • Signal Transduction
  • Uremic Toxins/adverse effects
  • chronic kidney disease
  • endothelial cells
  • vascular pathophysiology
  • ENDOPLASMIC-RETICULUM STRESS
  • endothelial dysfunction
  • LOW-DENSITY LIPOPROTEINS
  • CARDIOVASCULAR-DISEASE
  • SMOOTH-MUSCLE-CELLS
  • PROTEIN CARBAMYLATION
  • GLYCATION END-PRODUCTS
  • cardiovascular disease
  • OXIDATIVE STRESS
  • uremic toxins
  • VASCULAR CALCIFICATION
  • DOWN-REGULATION
  • P-CRESYL SULFATE
  • vascular dysfunction

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