Overexpression of hyaluronan synthase 2 alters hyaluronan distribution and function in proximal tubular epithelial cells

被引:41
作者
Selbi, Wisam
Day, Anthony J.
Rugg, Marilyn S.
Fulop, Csaba
de la Motte, Carol A.
Bowen, Timothy
Hascall, Vincent C.
Phillips, Aled O.
机构
[1] Univ Cardiff, Sch Med, Inst Nephrol, Cardiff CF14 4XN, Wales
[2] Univ Oxford, Dept Biochem, MRC, Immunochem Unit, Oxford OX1 3QU, England
[3] Cleveland Clin Fdn, Sect Connect Tissue Biol, Dept Biomed Engn, Cleveland, OH 44195 USA
[4] Cleveland Clin Fdn, Dept Immunol, Cleveland, OH 44195 USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2006年 / 17卷 / 06期
基金
英国医学研究理事会;
关键词
D O I
10.1681/ASN.2005080879
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
The functional consequences of increased renal cortical hyaluronan that is associated with both acute injury and progressive scarring are unclear. The aim of this study was to characterize hyaluronan synthase-2 (HAS2)-driven HA synthesis and determine its effect on renal proximal tubular epithelial cell (PTC) function, because this is known to be the inducible form of HA synthase in this cell type. Overexpression of HAS2 mRNA increased HA generation, which in the supernatant predominantly was HA of large molecular weight, whereas there was an increase in low molecular weight HA in cell-associated fractions. This was associated with increased expression of hyaluronidases, inhibition of HA cable formation concurrent with reduction in HA-dependent monocyte binding, and increased pericellular HA matrix. Overexpression of HAS2 led to enhanced cell migration. HA can be modified by the covalent attachment of heavy chains that are derived from the serum protein inter-a-inhibitor (I alpha I), a process that is known to be catalyzed by TNF-alpha-stimulated gene 6 (TSG-6; an inflammation-associated protein). Enhanced migration was abrogated by blocking antibodies to either I alpha I or TSG-6. Addition of recombinant full-length TSG-6 (TSG-6Q) or TSG-6Q-Y94F, a mutant variant with impaired HA binding, increased cell migration. Both of these proteins were able to mediate the covalent transfer of heavy chains, from I alpha I and pre-alpha-inhibitor, onto HA. Addition of the isolated TSG-6-Link module (Link_TSG-6), which binds HA but is unable to form covalent complexes with I alpha I/pre-alpha-inhibitor, had no effect on migration, suggesting that TSG-6-mediated formation of heavy chain-HA complexes is critical in the formation of a pericellular HA matrix.
引用
收藏
页码:1553 / 1567
页数:15
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