TY - JOUR
T1 - Urea Memory
T2 - Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction
AU - d'Apolito, Maria
AU - Colia, Anna Laura
AU - Manca, Enrica
AU - Pettoello-Mantovani, Massimo
AU - Sacco, Michele
AU - Maffione, Angela Bruna
AU - Brownlee, Michael
AU - Giardino, Ida
PY - 2018/10/11
Y1 - 2018/10/11
N2 - 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.
AB - 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.
KW - cardiovascular disease
KW - chronic renal failure
KW - CRF
KW - CVD
KW - end stage renal disease
KW - ESRD
KW - reactive oxygen species
KW - ROS
KW - urea
KW - uremic memory
UR - http://www.scopus.com/inward/record.url?scp=85054898663&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054898663&partnerID=8YFLogxK
U2 - 10.3390/toxins10100410
DO - 10.3390/toxins10100410
M3 - Article
C2 - 30314315
AN - SCOPUS:85054898663
VL - 10
JO - Toxins
JF - Toxins
SN - 2072-6651
IS - 10
ER -