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Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes

Eva Schepers UGent, Griet Glorieux UGent, Annemieke Dhondt UGent, Luc Leybaert UGent and Raymond Vanholder UGent (2009) NEPHROLOGY DIALYSIS TRANSPLANTATION. 24(5). p.1429-1435
abstract
BACKGROUND: The guanidines asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, and its counterpart symmetric dimethylarginine (SDMA), considered inert, are accumulated in chronic kidney disease (CKD). The present study evaluates their effect on monocyte function, since previous data demonstrated leukocyte activation by other guanidino compounds. METHODS: The effect of ADMA and SDMA on reactive oxygen species (ROS) production in human whole blood at baseline and after N-formyl-methionine-leucine-phenylalanine (fMLP) stimulation was evaluated. By using the fluorescent probe Fluo3-AM, the role of changes in monocytic cytoplasmic calcium ([Ca(2+)](i)) was studied. Thapsigargin, and removal followed by addition of extracellular Ca(2+) (Ca(2+)(ex)), was used to investigate the contribution of store-operated Ca(2+)-channels (SOCs). SKF96365 was used as a selective inhibitor of the SOCs. A pharmacologic intervention with captopril, known to affect Ca(2+) influx, was tested. RESULTS: SDMA enhanced ROS production in fMLP-stimulated monocytes using heparinized blood, and this effect was abolished in EDTA-anticoagulated blood. In the presence of SDMA, an increased Ca(2+) entry from the extracellular milieu resulted in an elevated amplitude of the peak [Ca(2+)](i) change triggered by fMLP. None of these effects were seen with ADMA. Depletion of the intracellular stores with thapsigargin in the absence of Ca(2+)(ex), followed by re-addition of Ca(2+)(ex) triggered a significantly larger Ca(2+) entry after SDMA treatment versus saline. This effect was prevented with SKF96365, as was the SDMA-enhanced oxidative burst after fMLP. Pre-incubation with captopril also reduced the increased ROS production seen with SDMA. CONCLUSIONS: SDMA, a uraemic retention solute considered inert, stimulates ROS production of monocytes by acting on Ca(2+) entry via SOCs. This pro-inflammatory effect may trigger vascular pathology and may be involved in altering the prevalence of cardiovascular disease in CKD.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MORTALITY, IN-VITRO, MAINTENANCE HEMODIALYSIS, HEMODIALYSIS-PATIENTS, CARDIOVASCULAR-DISEASE, ASYMMETRICAL DIMETHYLARGININE, CHRONIC-RENAL-FAILURE, CORONARY-ARTERY-DISEASE, CHRONIC KIDNEY-DISEASE, UREMIC RETENTION SOLUTES, reactive oxygen species, leukocytes, guanidines, chronic kidney disease, calcium
journal title
NEPHROLOGY DIALYSIS TRANSPLANTATION
Nephrol. Dial. Transplant.
volume
24
issue
5
pages
1429 - 1435
Web of Science type
Article
Web of Science id
000265275000016
JCR category
UROLOGY & NEPHROLOGY
JCR impact factor
3.306 (2009)
JCR rank
13/61 (2009)
JCR quartile
1 (2009)
ISSN
0931-0509
DOI
10.1093/ndt/gfn670
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
525769
handle
http://hdl.handle.net/1854/LU-525769
date created
2009-03-19 12:04:02
date last changed
2010-09-02 13:33:24
@article{525769,
  abstract     = {BACKGROUND: The guanidines asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, and its counterpart symmetric dimethylarginine (SDMA), considered inert, are accumulated in chronic kidney disease (CKD). The present study evaluates their effect on monocyte function, since previous data demonstrated leukocyte activation by other guanidino compounds. METHODS: The effect of ADMA and SDMA on reactive oxygen species (ROS) production in human whole blood at baseline and after N-formyl-methionine-leucine-phenylalanine (fMLP) stimulation was evaluated. By using the fluorescent probe Fluo3-AM, the role of changes in monocytic cytoplasmic calcium ([Ca(2+)](i)) was studied. Thapsigargin, and removal followed by addition of extracellular Ca(2+) (Ca(2+)(ex)), was used to investigate the contribution of store-operated Ca(2+)-channels (SOCs). SKF96365 was used as a selective inhibitor of the SOCs. A pharmacologic intervention with captopril, known to affect Ca(2+) influx, was tested. RESULTS: SDMA enhanced ROS production in fMLP-stimulated monocytes using heparinized blood, and this effect was abolished in EDTA-anticoagulated blood. In the presence of SDMA, an increased Ca(2+) entry from the extracellular milieu resulted in an elevated amplitude of the peak [Ca(2+)](i) change triggered by fMLP. None of these effects were seen with ADMA. Depletion of the intracellular stores with thapsigargin in the absence of Ca(2+)(ex), followed by re-addition of Ca(2+)(ex) triggered a significantly larger Ca(2+) entry after SDMA treatment versus saline. This effect was prevented with SKF96365, as was the SDMA-enhanced oxidative burst after fMLP. Pre-incubation with captopril also reduced the increased ROS production seen with SDMA. CONCLUSIONS: SDMA, a uraemic retention solute considered inert, stimulates ROS production of monocytes by acting on Ca(2+) entry via SOCs. This pro-inflammatory effect may trigger vascular pathology and may be involved in altering the prevalence of cardiovascular disease in CKD.},
  author       = {Schepers, Eva and Glorieux, Griet and Dhondt, Annemieke and Leybaert, Luc and Vanholder, Raymond},
  issn         = {0931-0509},
  journal      = {NEPHROLOGY DIALYSIS TRANSPLANTATION},
  keyword      = {MORTALITY,IN-VITRO,MAINTENANCE HEMODIALYSIS,HEMODIALYSIS-PATIENTS,CARDIOVASCULAR-DISEASE,ASYMMETRICAL DIMETHYLARGININE,CHRONIC-RENAL-FAILURE,CORONARY-ARTERY-DISEASE,CHRONIC KIDNEY-DISEASE,UREMIC RETENTION SOLUTES,reactive oxygen species,leukocytes,guanidines,chronic kidney disease,calcium},
  language     = {eng},
  number       = {5},
  pages        = {1429--1435},
  title        = {Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes},
  url          = {http://dx.doi.org/10.1093/ndt/gfn670},
  volume       = {24},
  year         = {2009},
}

Chicago
Schepers, Eva, Griet Glorieux, Annemieke Dhondt, Luc Leybaert, and Raymond Vanholder. 2009. “Role of Symmetric Dimethylarginine in Vascular Damage by Increasing ROS via Store-operated Calcium Influx in Monocytes.” Nephrology Dialysis Transplantation 24 (5): 1429–1435.
APA
Schepers, E., Glorieux, G., Dhondt, A., Leybaert, L., & Vanholder, R. (2009). Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes. NEPHROLOGY DIALYSIS TRANSPLANTATION, 24(5), 1429–1435.
Vancouver
1.
Schepers E, Glorieux G, Dhondt A, Leybaert L, Vanholder R. Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes. NEPHROLOGY DIALYSIS TRANSPLANTATION. 2009;24(5):1429–35.
MLA
Schepers, Eva, Griet Glorieux, Annemieke Dhondt, et al. “Role of Symmetric Dimethylarginine in Vascular Damage by Increasing ROS via Store-operated Calcium Influx in Monocytes.” NEPHROLOGY DIALYSIS TRANSPLANTATION 24.5 (2009): 1429–1435. Print.