Thyroid hormone receptor binding to DNA and T 3 -dependent transcriptional activation are inhibited by uremic toxins
- PDF / 575,063 Bytes
- 12 Pages / 610 x 792 pts Page_size
- 76 Downloads / 166 Views
BioMed Central
Open Access
Research
Thyroid hormone receptor binding to DNA and T3-dependent transcriptional activation are inhibited by uremic toxins Guilherme M Santos1,3, Carlos J Pantoja1, Aluízio Costa e Silva2, Maria C Rodrigues1, Ralff C Ribeiro, Luiz A Simeoni1, Noureddine Lomri3 and Francisco AR Neves*1 Address: 1Molecular Pharmacology Laboratory, Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brazil, 2SOCLIMED – Dialysis Unit, Brasília, Brazil and 3University of Cergy-Pontoise, UFR des Sciences et Techniques, ERRMECe Laboratory, BP222, 2 Ave Adolphe Chauvin, 95302 Cergy-Pontoise, France Email: Guilherme M Santos - [email protected]; Carlos J Pantoja - [email protected]; Aluízio Costa e Silva - [email protected]; Maria C Rodrigues - [email protected]; Ralff C Ribeiro - [email protected]; Luiz A Simeoni - [email protected]; Noureddine Lomri - [email protected]; Francisco AR Neves* - [email protected] * Corresponding author
Published: 04 April 2005 Nuclear Receptor 2005, 3:1
doi:10.1186/1478-1336-3-1
Received: 30 November 2004 Accepted: 04 April 2005
This article is available from: http://www.nuclear-receptor.com/content/3/1/1 © 2005 Santos et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: There is a substantial clinical overlap between chronic renal failure (CRF) and hypothyroidism, suggesting the presence of hypothyroidism in uremic patients. Although CRF patients have low T3 and T4 levels with normal thyroid-stimulating hormone (TSH), they show a higher prevalence of goiter and evidence for blunted tissue responsiveness to T3 action. However, there are no studies examining whether thyroid hormone receptors (TRs) play a role in thyroid hormone dysfunction in CRF patients. To evaluate the effects of an uremic environment on TR function, we investigated the effect of uremic plasma on TRβ1 binding to DNA as heterodimers with the retinoid X receptor alpha (RXRα) and on T3-dependent transcriptional activity. Results: We demonstrated that uremic plasma collected prior to hemodialysis (Pre-HD) significantly reduced TRβ1-RXRα binding to DNA. Such inhibition was also observed with a vitamin D receptor (VDR) but not with a peroxisome proliferator-activated receptor gamma (PPARγ). A cell-based assay confirmed this effect where uremic pre-HD ultrafiltrate inhibited the transcriptional activation induced by T3 in U937 cells. In both cases, the inhibitory effects were reversed when the uremic plasma and the uremic ultrafiltrate were collected and used after hemodialysis (Post-HD). Conclusion: These results suggest that dialyzable toxins in uremic plasma selectively block the binding of TRβ1-RXRα to DNA and impair T3 transcriptional activity. These findings may explain some features of hypothyroi
Data Loading...
