Hepatic messenger ribonucleic acid activity profiles in experimental azotemia in the rat. Relationship to food intake and thyroid function.

Abstract

A b:s tract. We have studied the hepatic messenger RNA (mRNA) activity profile in chronically azotemic rats and sought to determine whether the observed changes could be mediated either by reduced food intake or diminished thyroid function at the tissue level. mRNA activity profiles were produced by twodimensional gel electrophoretic separation of radioactively labeled products of an in vitro reticulocyte lysate system which had been programmed by hepatic RNA. Of the -240 translational products identified in this system, seven sequences were consistently altered in azotemia. In pair-fed animals six of these also decreased, but the alterations in three were depressed to a significantly lesser extent in the pair-fed group. Moreover, analysis of covariance suggested that food intake could account for the differences in only one sequence. The possibility that the mRNA activity profile in azotemia could represent the effects of diminished thyroid function was minimized by the finding that the reductions in plasma thyroxine (T4) and triiodothyronine (T3) levels observed were due largely to reduced plasma protein binding, with maintenance of the mean free T4 and free T3 concentrations within the normal range. The changes in only one mRNA sequence could be related to free T3 levels alone. Our findings, therefore, indicate that

Chronic Triiodothyronine Supplementation Does Not Improve the Lipoprotein Disorders of Mildly Uremic Rats

“…For Lim et al [2], the significant reduction in hepatic nuclear T, content and liver T, receptor-binding capacity in uremic rats with a severe degree of uremia (B U N >I g/1) was consistent with the presence of a selective tissue deficiency of thyroid hormone, in agreement with the observation of reduced activity of two liver enzymes (rx-GPD and ME) known to be under thyroid hormone regulation [1], It is important to note that uremic rats with a less severe degree of uremia (BUN < 1 g/1) showed only a trend to diminution but no statistically significant dif ference in hepatic nuclear Tj content and liver T; recep tor-binding capacity [2], Kinlaw et al [3] observed no significant reduction in the hepatic level of nuclear T, and in the activity of hepatic a-G PD and ME. These findings are consistent with a euthyroidal state of hepatic tissues in uremic rats associated with a normal circulating TSH level.…”

“…Finally, the discrepancy between results of Kinlaw et al [3] and Lim et al [1,2] may be related to the different duration of uremia in both studies (3 and 6 weeks, respec tively) and also to the degree of severity of uremia. A certain degree of uremia seems necessary for thyroid hormone dysfunction to become manifest because changes are more modest in the less azotemic group of rats.…”

“…In this experimental model of uremia thyroid dysfunc tion is reflected by a decrease in serum total T4 concentra tion associated with a normal serum total T, level, sim ilarly to the results obtained by Lim et al [1] in rats 5 weeks after initiating chronic renal failure. In another report, Kinlaw et al [3] observed a marked decrease in plasma total T4 and plasma total T, levels in azotemic rats 3 weeks only after initiating the uremic state. These de creases were however due to reduced plasma protein binding with maintenance of free Tj and free T4 concen trations within the normal range.…”

“…It has also been reported that the concentration of circulating T3 was reduced in uremic rats leading to hypothyroidism at the tissue level as reflected by reduced activities of two highly T3-responsive hepatic enzymes, i.e., alpha-glycerol phos phate dehydrogenase (cx-GPD) and malic enzyme (ME) [1,2]. However, a recent report by Kinlaw et al [3] indi cated an euthyroidal state of hepatic tissue in uremic rats in the presence of an important reduction in plasma T3 and T4 levels.…”

Digitalis in Chronic Renal Insufficiency

“…Abnormalities for all these hormones have been described in uremia [41][42][43]. In particular, tissue level hypothyroidism has been found in previous studies [43], although this has not been confirmed in more recent investigations [44], Further information on receptor occupan cy, binding kinetics and postbinding events in uremia are required before the effects of inhibition of Na.K-ATP'ase by hypothetical endogenous inhibitors on the response to ex ogenous digitalis can be assessed. At the mo ment, no clear clinical consequences can be derived from the above considerations.…”