Abstract
BackgroundThere 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.ResultsWe 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).ConclusionThese 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 hypothyroidism and thyroid hormone resistance observed in CRF patients.
Highlights
There is a substantial clinical overlap between chronic renal failure (CRF) and hypothyroidism, suggesting the presence of hypothyroidism in uremic patients
Uremic plasma inhibits the binding of hTRβ1-hRXRα on DR-4 To study the effects of uremic plasma on the ability of TRβ1 to bind to a specific thyroid response elements (TREs) we analyzed the binding of hRXRα-hTRβ1 heterodimers to DR-4
thyroid hormone receptors (TRs) incubation with uremic plasma collected prior to hemodialysis significantly reduced the binding of heterodimers (RXR-TR) to DR-4
Summary
There is a substantial clinical overlap between chronic renal failure (CRF) and hypothyroidism, suggesting the presence of hypothyroidism in uremic patients. 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. The peripheral thyroid hormone metabolism is altered in patients with CRF [5,6,7,8,9]. Most CRF patients, are considered to be euthyroid as evidenced by normal thyroidstimulating hormone (TSH) levels [11,13]. The prevalence of thyroid diseases, including goiter and hypothyroidism, are higher in CRF patients than in the general population [10]
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