UNIGE document Scientific Article
previous document  unige:46797  next document
add to browser collection
Title

Synthesis of anticoagulantly active heparan sulfate proteoglycans by glomerular epithelial cells involves multiple 3-O-sulfotransferase isoforms and a limiting precursor pool

Authors
Hajmohammadi, Sassan
Helisch, Armin
Shworak, Nicholas W
Published in Journal of Biological Chemistry. 2005, vol. 280, no. 45, p. 38059-38070
Abstract Endothelial and other select cell types synthesize a subpopulation of heparan sulfate (HS) proteoglycans (HSPGs), anticoagulant HSPGs (aHSPGs) that bear aHS-HS chains with the cognate 3-O-sulfated pentasaccharide motif that can bind and activate anti-thrombin (AT). Endothelial cells regulate aHSPG production by limiting levels of HS 3-O-sulfotransferase-1 (3-OST-1), which modifies a non-limiting pool of aHS-precursors. By probing kidney cryosections with (125)I-AT and fluorescently tagged AT we found that the glomerular basement membrane contains aHSPGs, with the staining pattern implicating synthesis by glomerular epithelial cells (GECs). Indeed, cultured GECs synthesized aHS with high AT affinity that was comparable with the endothelial product. Disaccharide analyses of human GEC (hGEC) HS in conjunction with transcript analyses revealed that hGECs express predominantly 3-OST-1 and 3-OST-3(A). aHS production has not been previously examined in cells expressing multiple 3-OST isoforms. This unusual situation appears to involve novel mechanisms to regulate aHS production, as HS structural analyses suggest hGECs exhibit excess levels of 3-OST-1 and an extremely limiting pool of aHS-precursor. A limiting aHS-precursor pool may serve to minimize aHS synthesis by non-3-OST-1 isoforms. Indeed, we show that high in vitro levels of 3-OST-3(A) can efficiently generate aHS. Non-3-OST-1 isoforms can generate aHS in vivo, as the probing of kidney sections from 3-OST-1-deficient mice revealed GEC synthesis of aHSPGs. Surprisingly, Hs3st1(-/-) kidney only expresses 3-OST isoforms having a low specificity for aHS synthesis. Thus, our analyses reveal a cell type that expresses multiple 3-OST isoforms and produces minimal amounts of aHS-precursor. In part, this mechanism should prevent aHS overproduction by non-3-OST-1 isoforms. Such a role may be essential, as 3-OST isoforms that have a low specificity for aHS synthesis can generate substantial levels of aHSPGs in vivo.
Keywords AnimalsAnticoagulants/metabolismCells, CulturedEpithelial Cells/enzymology/metabolismGene DeletionGene Expression RegulationHeparan Sulfate Proteoglycans/biosynthesisIsoenzymes/metabolismKidney Glomerulus/cytology/enzymologyMaleMiceRNA, Messenger/metabolismRatsRats, Sprague-DawleySulfotransferases/genetics/metabolism
Identifiers
PMID: 16107334
Full text
Article (Published version) (1.2 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Research group Pathogénèse du syndrome néphrotique idiopathique de l'enfant (180)
Citation
(ISO format)
GIRARDIN, Eric et al. Synthesis of anticoagulantly active heparan sulfate proteoglycans by glomerular epithelial cells involves multiple 3-O-sulfotransferase isoforms and a limiting precursor pool. In: Journal of Biological Chemistry, 2005, vol. 280, n° 45, p. 38059-38070. https://archive-ouverte.unige.ch/unige:46797

142 hits

0 download

Update

Deposited on : 2015-02-18

Export document
Format :
Citation style :