Thyroid hormone receptor binding to DNA and T3-dependent transcriptional activation are inhibited by uremic toxins

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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 T ₃and T ₄levels with normal thyroid-stimulating hormone (TSH), they show a higher prevalence of goiter and evidence for blunted tissue responsiveness to T ₃action. 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 T ₃-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 T ₃in 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 T ₃transcriptional activity. These findings may explain some features of hypothyroidism and thyroid hormone resistance observed in CRF patients.

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The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different "orphan" receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metabolism such as fatty acids, prostaglandins, or cholesterol derivatives can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by "cross-talking" to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compactation and transcriptional repression. Upon ligand binding, the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity, whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompactation and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the specific interaction motifs in the receptors, has demonstrated the existence of a general molecular mechanism by which different receptors elicit their transcriptional responses in target genes.

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Author and article information

Journal

Journal ID (nlm-ta): Nucl Recept

Title: Nuclear Receptor

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-1336

Publication date Collection: 2005

Publication date (Electronic): 4 April 2005

Volume: 3

Page: 1

Affiliations

[1 ]Molecular Pharmacology Laboratory, Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasilia, Brazil

[2 ]SOCLIMED – Dialysis Unit, Brasília, Brazil

[3 ]University of Cergy-Pontoise, UFR des Sciences et Techniques, ERRMECe Laboratory, BP222, 2 Ave Adolphe Chauvin, 95302 Cergy-Pontoise, France

Article

Publisher ID: 1478-1336-3-1

DOI: 10.1186/1478-1336-3-1

PMC ID: 1087878

PubMed ID: 15807894

SO-VID: 0675fa4d-ce6b-43e1-805a-263cc6aa24b7

License:

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.

History

Date received : 30 November 2004

Date accepted : 4 April 2005

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