Uremic Toxin Indoxyl Sulfate Promotes Macrophage-Associated Low-Grade Inflammation and Epithelial Cell Senescence

Andrea Ribeiro, Feiyue Liu, Matthias Srebrzynski, Simone Rother, Karina Adamowicz, Marta Wadowska, Stefanie Steiger, Hans Joachim Anders, Christoph Schmaderer, Joanna Koziel, Maciej Lech

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

In this study, we investigated the impact of the uremic toxin indoxyl sulfate on macrophages and tubular epithelial cells and its role in modulating the response to lipopolysaccharide (LPS). Indoxyl sulfate accumulates in the blood of patients with chronic kidney disease (CKD) and is a predictor of overall and cardiovascular morbidity/mortality. To simulate the uremic condition, primary macrophages and tubular epithelial cells were incubated with indoxyl sulfate at low concentrations as well as concentrations found in uremic patients, both alone and upon LPS challenge. The results showed that indoxyl sulfate alone induced the release of reactive oxygen species and low-grade inflammation in macrophages. Moreover, combined with LPS (proinflammatory conditions), indoxyl sulfate significantly increased TNF-α, CCL2, and IL-10 release but did not significantly affect the polarization of macrophages. Pre-treatment with indoxyl sulfate following LPS challenge induced the expression of aryl hydrocarbon receptor (Ahr) and NADPH oxidase 4 (Nox4) which generate reactive oxygen species (ROS). Further, experiments with tubular epithelial cells revealed that indoxyl sulfate might induce senescence in parenchymal cells and therefore participate in the progression of inflammaging. In conclusion, this study provides evidence that indoxyl sulfate provokes low-grade inflammation, modulates macrophage function, and enhances the inflammatory response associated with LPS. Finally, indoxyl sulfate signaling contributes to the senescence of tubular epithelial cells during injury.

Original languageEnglish
Article number8031
JournalInternational Journal of Molecular Sciences
Volume24
Issue number9
DOIs
StatePublished - May 2023
Externally publishedYes

Keywords

  • CKD
  • indoxyl sulfate
  • inflammaging
  • inflammation
  • macrophage
  • senescence
  • uremic toxins

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