Uremic toxins promote accumulation of oxidized protein and increased sensitivity to hydrogen peroxide in endothelial cells by impairing the autophagic flux

Silvia D. Rodrigues, Sabrina S. Santos, Tassiana Meireles, Natalia Romero, Griet Glorieux, Roberto Pecoits-Filho, Donna D. Zhang, Lia S. Nakao

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Chronic kidney disease (CKD) is associated with high mortality rates, mainly due to cardiovascular diseases (CVD). Uremia has been considered a relevant risk factor for CVD in CKD patients, since uremic toxins (UTs) promote systemic and vascular inflammation, oxidative stress and senescence. Here, we demonstrate that uremic toxins indoxyl sulfate (IxS), p-cresyl sulfate (pCS) and indole acetic acid (IAA) are incorporated by human endothelial cells and inhibit the autophagic flux, demonstrated by cellular p62 accumulation. Moreover, isolated and mixed UTs impair the lysosomal stage of autophagy, as determined by cell imaging of the mRFP-GFP-LC3 protein. Endothelial cells exposed to UTs display accumulation of carbonylated proteins and increased sensitivity to hydrogen peroxide. Rapamycin, an autophagy activator which induces both autophagosome formation and clearance, prevented these effects. Collectively, our findings demonstrate that accumulation of oxidized proteins and enhanced cell sensitivity to hydrogen peroxide are consequences of impaired autophagic flux. These data provide evidence that UTs-induced impaired autophagy may be a novel contributor to endothelial dysfunction.

Original languageEnglish (US)
Pages (from-to)123-129
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume523
Issue number1
DOIs
StatePublished - Feb 26 2020

Keywords

  • Autophagy impairment
  • Chronic kidney disease
  • Oxidative stress
  • Protein carbonylation
  • Uremic toxins

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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