Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/31860
Title: Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells.
Authors: Abbasian, Nima
Burton, James O.
Herbert, Karl E.
Tregunna, Barbara-Emily
Brown, Jeremy R.
Ghaderi-Najafabadi, Maryam
Brunskill, Nigel J.
Goodall, Alison H.
Bevington, Alan
First Published: 5-Mar-2015
Publisher: American Society of Nephrology
Citation: Journal of the American Society of Nephrology 26: 2015
Abstract: Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.
DOI Link: 10.1681/ASN.2014070642
ISSN: 1046-6673
eISSN: 1533-3450
Links: http://jasn.asnjournals.org/content/early/2015/03/03/ASN.2014070642
http://hdl.handle.net/2381/31860
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2015 by the American Society of Nephrology. Archived with reference to SHERPA/RoMEO and publisher website. Version of record: http://jasn.asnjournals.org/content/early/2015/03/03/ASN.2014070642
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

Files in This Item:
File Description SizeFormat 
Abbasian et al JASN 2015.pdfPost-review (final submitted)1.34 MBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.