Regulation of conversion of thyroxine to triiodothyronine in perfused rat kidney

Abstract

The factors regulating the renal uptake of thyroxine (T4), its conversion to 3,5,3'-triiodothyronine (T3), and the urinary iodothyronine excretion were studied in the perfused rat kidney. Increasing the perfusate free T4 (FT4) concentration from 1 to 11.5 times that of euthyroid rat serum resulted in a linear increase in T4 uptake and T3 production that was not saturated at the highest dose. When FT4 concentrations were increased by decreasing the perfusate albumin concentration from 7.5 to 2.5 g/dl, T4 uptake and T3 production increased in proportion to the FT4 concentration. Propylthiouracil (PTU), a 5'-deiodinase inhibitor, decreased renal T3 production by 60.5% without affecting tissue T4 uptake. In the absence of glomerular filtration, T4 uptake and T3 production were unchanged, indicating that T4 is extracted by the contraluminal surface of the renal tubule. However, probenecid, an inhibitor of contraluminal organic acid uptake, did not decrease but increased T4 uptake and T3 production by increasing the perfusate FT4 fraction in the perfusate. There was no net renal 3,3',5'-triiodothyronine (rT3) production from T4, and degradation and urinary excretion of T3 were negligible. The urinary excretion of T4 and T3 correlated closely with the degree of proteinuria.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Addition of PTU decreases renal T 3 production by about 60% without affecting tissue T 4 uptake, illustrating the presence of D1. In this setting there is no net renal rT 3 production from T 4 , and degradation and urinary excretion of T 3 are negligible (174)(175)(176).…”

Stereospecific Triiodothyronine Binding Sites in Rabbit Renal Apical Membranes and Their Functional Role in the Proximal Tubule

“…This latter finding contrasts with the importance of the degree of iodination of thy roid hormone analogues for optimal binding to the serum transport proteins, such as thy roxine-binding globulin and thyroxine-bind ing prealbumin, or nuclear receptor [2,32], In agreement with the present data, however, studies using erythrocyte plasma membranes have shown that the iodine at position 5' is not critical for thyroid hormone analogues binding to rabbit erythrocyte membranes [33] and in the activation of Ca2+ ATPase in hu man red cell membrane ghosts [34], The data reported herein demonstrate a generally good correlation between the relative affinity of thyroid hormone analogues for brush border membranes and their relative in vivo biologi cal activity except that the luminal binding sites show equal affinity for T 3 and the less biologically active T4. However, the conver sion of T4 to T 3 is an important function of the liver and kidneys in contributing to the level of intracellular T 3 in various target tis sues that are incapable of converting T 4 to T 3 [11,35,36], Accordingly, this result may not be surprising if it is assumed that these apical binding sites have a functional role in the recovery by renal cells of T4 filtered at the glo merulus, allowing its intracellular deiodination.…”

“…Conversely, there is evi dence that receptor-mediated endocytosis is one mechanism for T 3 entry into cultured mouse fibroblasts [5,7,8], GH3 cells [9] and rat skeletal myoblasts [ 10], Unexpectedly, in view of the potential im portance o f the kidney in the homeostatic reg ulation of T 3 and T 4 in the body fluids, the renal handling of these hormones is largely unknown. Studies in the isolated perfused rat kidney [ 11,12] have suggested that reabsorp tion of T 3 and T4 occurs by means of a highcapacity transport system. However, experi ments in the rat equilibrated with either [125I]-labeled T 3 or 3.3',5-triiodo-J9-thyronine (D-T 3) have suggested that transport of D-T 3 from plasma to cytosol in kidney occurs by an energy-dependent stereospecific process, whereas transmembrane T 3 transport is by simple diffusion [13].…”

Subcellular Distribution of Thyroxine 5'-Monodeiodinase Activity in Rabbit Kidney

“…Supporting this notion is the observation that certain membrane-stabilizing drugs reduce the activity of 6'-deiodination in isolated renal tubule preparations but not in renal homogenate preparations (Heyma, Larkins and Campbell 1980). In addition, recent work utilizing an isolated kidney perfusion system has indicated that 5'-DI activity is localized on the basolateral membrane of the renal tubules (Ferguson and Jennings 1983). In the present study, we demonstrated that the basolateral membrane and microsomal fractions had high T4 5'-DI activity in both the renal cortex and outer medulla.…”

“…A previous study of the subcellular distribution of 5'-DI in the rat kidney (Leonard and Rosenberg 1978) suggested that 5'-DI activity was highest in the microsomal fraction, where much of the brush border membrane (BBM) basolateral membrane and endoplasmic reticulum is recovered. Although recent studies have clarified that at least part of the cellular 5'-DI activity is localized in the basolateral membrane (BLM) (Ferguson and Jennings 1983), the definite localization of these reactions in the proximal tubules has not been elucidated. On the other hand, it is known that there are at least two different types of this enzyme (Silva, Leonard, Crantz and Larsen 1982).…”