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PMID: 15161634 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Hyaluronan attenuates transforming growth factor-beta1-mediated signaling in renal proximal tubular epithelial cells.

The American journal of pathology ·Vol. 164 ·No. 6 ·2004-06-00 ·Pages 1979-88

Ito T, Williams JD, Fraser D, Phillips AO

Abstract

Increased expression of hyaluronan (HA) has been associated with both acute renal injury and progressive renal disease, although the functional significance of this remains unclear. There is overwhelming evidence that transforming growth factor (TGF)-beta1 is critical to the development of progressive renal disease. Recent studies suggest an interaction between HA and TGF-beta signaling in cancer cell biology. The aim of this study was to examine the potential role of HA as a modulator of TGF-beta1 function in renal proximal tubular epithelial cells (PTC). Under resting conditions, co-localization of the principal receptor for HA, CD44, and both the TGF-beta type I and type II receptors was demonstrated by immunoprecipitation and western analysis and further confirmed by immunocytochemistry and confocal microscopy. Stimulation of PTC with TGF-beta1 led to increased synthesis of both type III and type IV collagen assessed by Western analysis. Addition of HA did not alter collagen synthesis, but abrogated TGF-beta1-mediated increase in type III and type IV collagen. This effect was blocked by the addition of a blocking antibody to CD44 and also by inhibition of MAP kinase kinase (MEK) activity. Furthermore HA decreased TGF-beta1 activation of a luciferase-SMAD responsive construct, and decreased translocation of SMAD4 into the cell nucleus. We have previously demonstrated an anti-migratory effect of TGF-beta1 in a scratch wounding model. As with HA antagonism of TGF-beta1 extracellular matrix generation, HA reduced the anti-migratory effect of TGF-beta1 in a CD44-dependent manner. In contrast to the effect of TGF-beta1 on collagen synthesis, which is SMAD-dependent, the anti-migratory effect of TGF-beta1 in this model is known to be dependent of activation of RhoA. In the presence of HA, TGF-beta1-mediated activation of RhoA was also abrogated in a CD44-dependent manner. The results suggest that co-localization of CD44 and TGF-beta receptors facilitate modulation of both SMAD and non-SMAD-dependent TGF-beta1-mediated events by HA. Our results therefore suggest that alteration of HA synthesis may represent an endogenous mechanism to limit renal injury.

MeSH Terms
Animals Antigens, CD/analysis Cell Line Cell Movement/drug effects,physiology Extracellular Matrix/drug effects,physiology Humans Hyaluronan Receptors/analysis Hyaluronic Acid/pharmacology Immunohistochemistry Kidney Tubules, Proximal/cytology,drug effects,physiology Rats Signal Transduction/drug effects,physiology Transfection Transforming Growth Factor beta/antagonists & inhibitors,pharmacology Transforming Growth Factor beta1 Urothelium/drug effects,immunology
Chemicals
Antigens, CD Hyaluronan Receptors TGFB1 protein, human Tgfb1 protein, rat Transforming Growth Factor beta Transforming Growth Factor beta1 Hyaluronic Acid
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ito Takafumi
Institute of Nephrology, University of Wales College of Medicine, Cardiff, Wales.
Williams John D
Fraser Donald
Phillips Aled O
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/s0002-9440(10)63758-3
Published
2004-06-00
Pages
1979-88
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1615759
Subset
IM
External Links
PubMed source DOI: 10.1016/s0002-9440(10)63758-3 PMC Full Text View journal details
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