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Toxins 2014, 6(6), 1742-1760; doi:10.3390/toxins6061742

Differential Effects of Indoxyl Sulfate and Inorganic Phosphate in a Murine Cerebral Endothelial Cell Line (bEnd.3)

1
Inserm U1088, Department of Pharmacy, 1 rue des Louvels, Amiens F-80037 Cédex 1, France
2
Université de Picardie Jules Verne, Amiens F-80025, France
3
University Medical Center of Amiens, Amiens F-80054, France
4
Division of Nephrology, Ambroise Paré University Medical Center, Paris, Boulogne Billancourt F-92100, France
5
Université Paris-Ile-de-France Ouest, Paris, Versailles F-78000, France
Present address: Departamento de Patologia Básica, Universidade Federal do Paraná, Curitiba 81540-970, Brazil
*
Author to whom correspondence should be addressed.
Received: 4 April 2014 / Revised: 17 May 2014 / Accepted: 26 May 2014 / Published: 4 June 2014
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Abstract

Endothelial dysfunction plays a key role in stroke in chronic kidney disease patients. To explore the underlying mechanisms, we evaluated the effects of two uremic toxins on cerebral endothelium function. bEnd.3 cells were exposed to indoxyl sulfate (IS) and inorganic phosphate (Pi). Nitric oxide (NO), reactive oxygen species (ROS) and O2 were measured using specific fluorophores. Peroxynitrite and eNOS uncoupling were evaluated using ebselen, a peroxide scavenger, and tetrahydrobiopterin (BH4), respectively. Cell viability decreased after IS or Pi treatment (p < 0.01). Both toxins reduced NO production (IS, p < 0.05; Pi, p < 0.001) and induced ROS production (p < 0.001). IS and 2 mM Pi reduced O2 production (p < 0.001). Antioxidant pretreatment reduced ROS levels in both IS- and Pi-treated cells, but a more marked reduction of O2 production was observed in Pi-treated cells (p < 0.001). Ebselen reduced the ROS production induced by the two toxins (p < 0.001); suggesting a role of peroxynitrite in this process. BH4 addition significantly reduced O2 and increased NO production in Pi-treated cells (p < 0.001), suggesting eNOS uncoupling, but had no effect in IS-treated cells. This study shows, for the first time, that IS and Pi induce cerebral endothelial dysfunction by decreasing NO levels due to enhanced oxidative stress. However, Pi appears to be more deleterious, as it also induces eNOS uncoupling. View Full-Text
Keywords: chronic kidney disease; uremic toxins; endothelial dysfunction; nitric oxide; reactive oxygen species chronic kidney disease; uremic toxins; endothelial dysfunction; nitric oxide; reactive oxygen species
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MDPI and ACS Style

Stinghen, A.E.M.; Chillon, J.-M.; Massy, Z.A.; Boullier, A. Differential Effects of Indoxyl Sulfate and Inorganic Phosphate in a Murine Cerebral Endothelial Cell Line (bEnd.3). Toxins 2014, 6, 1742-1760.

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