Thyroid Function in a Uremic Rat Model

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Abstract
The main objective of this study was to determine whether the principal abnormality of thyroid function observed in patients with chronic renal failure, low serum triiodothyronine (T3) concentration, causes hypothyroidism at the tissue level. A partially nephrectomized (Nx) uremic rat model was developed and the following parameters of thyroid function were assessed: serum total thyroxine (TT4), total T3 (TT3), and thyrotropin and liver T3 content, and activity of two thyroid hormone-dependent enzymes, mitochondrial α-glycerophosphate dehydrogenase (α-GPD) and cytosol malate dehydrogenase (MDH). The results were compared to those of intact control (C), thyroidectomized (Tx), and nephrectomized-thyroidectomized (NxTx) littermates. Results expressed as mean±SEM showed that Nx rats had a fivefold increase in blood urea nitrogen, (112±20 mg/dl in Nx, and 22±1 mg/dl in C) and manifested all the changes of of thyroid function observed in uremic men, including a low serum TT3 level (30±7 ng/dl in Nx and 50±6 ng/dl in C). In the liver, T3 was significantly reduced (18±2 ng/total liver in Nx and 35±3 ng/total liver in C) as well as the activities of αGPD (8.8±1.0 and 16.1±1.5 ΔOD/min per total liver in Nx and C, respectively) and MDH (6.3±1.6 and 12.6±2.2 U/total liver in Nx and C, respectively). The reduction in liver enzyme activities correlated significantly with the decrease in T3 content. The changes in Tx rats were as expected, showing a profound reduction in serum hormone levels, liver T3 content, and liver enzyme activities. Serum thyrotropin was markedly elevated to 2,390±212 ng/ml as compared to 703±61 in C and 441±87 ng/ml in Nx rats. The NxTx rats showed the combined effects of nephrectomy and thyroidectomy; blood urea nitrogen was elevated to 203, and serum levels of TT4, TT3, and thyrotropin were 0.4, 3 and αGPD and MDH were strikingly low; the corresponding values were 3.5, 2.4, and 2.5. l-triiodothyronine replacement (0.4 μg/100 g body wt/d) for 4 wk in the Nx rats resulted in significant increases in liver enzyme activities, αGPD and MDH rose by 70 and 60% over their respective basal values without alteration in the severity of azotemia. From these data, we conclude that the reduction of liver T3 content in the uremic rats, accompanied by a decrease in αGPD and MDH activity, indicates the presence of hypothyroidism at the tissue level. Restoration of enzyme activities toward normal levels after T3 administration provided further supporting evidence that the diminution in liver enzyme activity was causally related to tissue T3 deficiency.