The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair.
BACKGROUND
Cardiovascular diseases are the major causes of mortality in uremic patients, and the vascular endothelium is dysfunctional in uremia. We hypothesized that uremic retention solutes may be among the factors involved in this endothelial dysfunction. We therefore investigated the in vitro effect of a large panel of uremic retention solutes (guanidino compounds, polyamines, oxalate, myoinositol, urea, uric acid, creatinine, indoxyl sulfate, indole-3-acetic acid, p-cresol, hippuric acid, and homocysteine) on endothelial proliferation. In addition, we tested the effect of uremic solutes that altered proliferation on endothelial wound repair.


METHODS
Human umbilical vein endothelial cells (HUVEC) were incubated with uremic retention solutes at concentrations in the range found in uremic patients. Protein-bound uremic solutes were also tested in the presence of 4% human albumin. Then, we determined the effect of each uremic solute on endothelial proliferation by a 5-bromo-2-deoxy-uridine (BrdU) labeling assay. In addition, confluent endothelial monolayers were injured, incubated with uremic solutes that altered endothelial proliferation, and the surface of the wound was measured at different intervals by image analysis.


RESULTS
Endothelial proliferation was inhibited by two protein-bound uremic retention solutes: p-cresol and indoxyl-sulfate. Inhibition of endothelial proliferation by p-cresol was dose-dependent. Moreover, p-cresol and indoxyl sulfate decreased endothelial wound repair. The presence of albumin did not affect the inhibitory effect of these solutes on endothelial proliferation, but the decrease in endothelial wound repair was less marked in the presence of albumin.


CONCLUSIONS
We demonstrated that both p-cresol and indoxyl sulfate decrease endothelial proliferation and wound repair. These solutes could play a role in endothelial dysfunction observed in uremic patients.
Dou
Laetitia
L
INSERM EMI0019, UFR de Pharmacie, Université de la Méditerranée, Marseille, France. laetitia.dou@pharmacie.univ-mrs.fr
Bertrand
Emilie
E
Cerini
Claire
C
Faure
Valerie
V
Sampol
Jose
J
Vanholder
Raymond
R
Berland
Yvon
Y
Brunet
Philippe
P
D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003408:Cresols / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D007200:Indican / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D014511:Uremia / Q000378:metabolism* / Q000473:pathology*; D014945:Wound Healing
D003408:Cresols; C032538:4-cresol; D007200:Indican