Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction

Maria d'Apolito, Anna Laura Colia, Enrica Manca, Massimo Pettoello-Mantovani, Michele Sacco, Angela Bruna Maffione, Michael Brownlee, Ida Giardino

Research output: Contribution to journalArticlepeer-review

Abstract

Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis.

Original languageEnglish
JournalToxins
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 11 2018

Keywords

  • cardiovascular disease
  • chronic renal failure
  • CRF
  • CVD
  • end stage renal disease
  • ESRD
  • reactive oxygen species
  • ROS
  • urea
  • uremic memory

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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