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Iodine and the Body
Kidney pg 3
PAVELKA, BABICKY, VOBECKY
Biological half-life of bromide in the rat depends primarily on the magnitude of sodium intake.
Pavelka S, Babicky A, Vobecky M.
Physiol Res. 2005;54(6):639-44.
The parallel course of the excretion rates of bromide and sodium ions was demonstrated in adult male and female rats administered
simultaneously with potassium 82Br-bromide and 24Na-sodium chloride. The animals were exposed to various intakes of sodium ions
accompanied with five different anions: Br-, Cl-, HCO3-, ClO4-, and SCN-. Regardless of the anion accompanying the sodium ion, the
excretion rates of 82Br- and 24Na+ ions were proportional to the magnitude of sodium intake in the animals. Hence, we have proved
our hypothesis that the biological half-life of bromide depends on the magnitude of sodium intake rather than on the intake of chlorid
Biological half-lives of bromide and sodium in the rat are connected and dependent on the physiological state.
Babicky A, Pavelka S, Vobecky M.
Biol Trace Elem Res. 2005 Jan;103(1):49-58.
[abstract only]
The parallel course of the excretion rates of sodium and bromide ions was demonstrated in adult male rats administered
simultaneously with 24Na-sodium chloride and 82Br-bromide. These excretion rates were inversely proportional to the magnitude of
sodium intake in the animals. The biological half-life of bromide, as a substitute for sodium or chloride, was investigated with the aid
of the radionuclide 82Br in animals situated in very different physiological states (i.e., in lactating and nonlactating female rats as
well as in young rats of varying ages [2, 4, 6, and 10 wk of age]). The 82Br radioactivity retained in mothers and in whole litters was
measured in vivo at appropriate time intervals (up to 240 h) after the application of 82Br-bromide to the mothers. The time-course of
the changes in the 82Br radioactivity of the young was calculated as the difference between the rate of 82Br intake in the mother's
milk and the 82Br excretion through the kidneys into the urine. The rate of 82Br excretion through the kidneys of the dam could be
calculated also. Nonweaned young rats (12 d) had the highest half-life (269 h) and lactating dams had the lowest (44 h). The
determined values demonstrated that nonweaned young apparently conserve sodium, because of its relatively low concentration in
mother's milk, whereas lactating dams, because of their large food intake, waste sodium.
Metabolism of bromide and its interference with the metabolism of iodine.
Pavelka S.
Physiol Res. 2004;53 Suppl 1:S81-90. Review.
The present knowledge about the metabolism of bromide with respect to its goitrogenic effects, including some conclusions drawn
from our recent research on this subject, is reviewed. Firstly, the biological behavior of bromide ion is compared with that of chloride
and iodide. Secondly, the details about distribution and kinetics of bromide ions in the body and in 15 different organs and tissues of
the rat are given. Significant correlation between the values of the steady-state concentration of bromide in the respective tissue and
of the corresponding biological half-life was found in most tissues examined. A remarkably high concentration of radiobromide was
found in the skin, which represents, due to its large mass, the most abundant depot of bromide in the body of the rat. Thirdly, the
effects of excessive bromide on the rat thyroid are summarized, along with the interference of exogenous bromide with the
whole-body metabolism of iodine. It is suggested that high levels of bromide in the organism of experimental animals can influence
their iodine metabolism in two parallel ways: by a decrease in iodide accumulation in the thyroid and skin (and in the mammary
glands in lactating dams), and by a rise in iodide excretion by kidneys. By accelerating the renal excretion of iodide, excessive
bromide can also influence the pool of exchangeable iodide in the thyroid. Finally, our recent results concerning the influence of
high bromide intake in the lactating rat dam on iodine and bromide transfer to the suckling, and the impact of seriously decreased
iodine content and increased bromide concentration in mother's milk on the young are discussed. We must state, however, that the
virtue of the toxic effects of excessive bromide on the thyroid gland and its interference with the biosynthesis of thyroid hormones, as
well as the exact mechanism of bromide interference with postnatal developmental processes remains to be elucidated.
Biological half-lives of bromide and sodium in the rat are connected and dependent on the physiological state.
Babicky A, Pavelka S, Vobecky M.
Biol Trace Elem Res. 2005 Jan;103(1):49-58.
[abstract only]
The parallel course of the excretion rates of sodium and bromide ions was demonstrated in adult male rats administered
simultaneously with 24Na-sodium chloride and 82Br-bromide. These excretion rates were inversely proportional to the magnitude of
sodium intake in the animals. The biological half-life of bromide, as a substitute for sodium or chloride, was investigated with the aid
of the radionuclide 82Br in animals situated in very different physiological states (i.e., in lactating and nonlactating female rats as
well as in young rats of varying ages [2, 4, 6, and 10 wk of age]). The 82Br radioactivity retained in mothers and in whole litters was
measured in vivo at appropriate time intervals (up to 240 h) after the application of 82Br-bromide to the mothers. The time-course of
the changes in the 82Br radioactivity of the young was calculated as the difference between the rate of 82Br intake in the mother's
milk and the 82Br excretion through the kidneys into the urine. The rate of 82Br excretion through the kidneys of the dam could be
calculated also. Nonweaned young rats (12 d) had the highest half-life (269 h) and lactating dams had the lowest (44 h). The
determined values demonstrated that nonweaned young apparently conserve sodium, because of its relatively low concentration in
mother's milk, whereas lactating dams, because of their large food intake, waste sodium.
Metabolism of bromide and its interference with the metabolism of iodine.
Pavelka S.
Physiol Res. 2004;53 Suppl 1:S81-90. Review.
The present knowledge about the metabolism of bromide with respect to its goitrogenic effects, including some conclusions drawn
from our recent research on this subject, is reviewed. Firstly, the biological behavior of bromide ion is compared with that of chloride
and iodide. Secondly, the details about distribution and kinetics of bromide ions in the body and in 15 different organs and tissues of
the rat are given. Significant correlation between the values of the steady-state concentration of bromide in the respective tissue and
of the corresponding biological half-life was found in most tissues examined. A remarkably high concentration of radiobromide was
found in the skin, which represents, due to its large mass, the most abundant depot of bromide in the body of the rat. Thirdly, the
effects of excessive bromide on the rat thyroid are summarized, along with the interference of exogenous bromide with the
whole-body metabolism of iodine. It is suggested that high levels of bromide in the organism of experimental animals can influence
their iodine metabolism in two parallel ways: by a decrease in iodide accumulation in the thyroid and skin (and in the mammary
glands in lactating dams), and by a rise in iodide excretion by kidneys. By accelerating the renal excretion of iodide, excessive
bromide can also influence the pool of exchangeable iodide in the thyroid. Finally, our recent results concerning the influence of
high bromide intake in the lactating rat dam on iodine and bromide transfer to the suckling, and the impact of seriously decreased
iodine content and increased bromide concentration in mother's milk on the young are discussed. We must state, however, that the
virtue of the toxic effects of excessive bromide on the thyroid gland and its interference with the biosynthesis of thyroid hormones, as
well as the exact mechanism of bromide interference with postnatal developmental processes remains to be elucidated.
The effect of bromide on the ultrastructure of rat thyrocytes.
Velicky J, Titlbach M, Lojda Z, Duskova J, Vobecky M, Raska I.
Ann Anat. 2004 Jun;186(3):209-16.
[abstract only]
"Electron microscopic examination of thyroid tissue following administration of bromide to rats showed marked hypertrophy and
hyperplasia in the thyrocytes, microfollicular rearrangement and lowered volume of colloid. The luminal surface of the thyrocytes
showed increased size and number of microvilli, often filling the microlumen. Most of the nuclei were irregular in shape with unusual
incisions and a higher density of chromatin. Proliferation of ER was seen with significantly dilated cisterns containing low electron
density material. The Golgi complex was well developed and larger in rats receiving 10 mg Br/l drinking water (16 days) and 100 mg
Br/l (16 and 66 days) than in control rats. Granules and small spherical structures (50-100 nm) appeared in the subapical part of the
cytoplasm and their number increased in animals after administration of 50 mg Br-/l (16 and 66 days), 100 mg Br-/l (16 and 66 days),
200 and 400 mg Br-/l (133 days). In contrast, their number was reduced in thyrocytes of rats treated with 100 mg Br/l (16, 66 and 133
days). Colloid droplets were only rarely found. There was no significant change in the amount of mitochondria, secondary lysosomes
including phagolysosomes. Some thyrocytes showed signs of necrosis in animals following administration of 10 mg Br/l (16 days, 100
and 400 mg Br/l, 133 days). Clusters of thyrocytes with spongy cytoplasm and bizarre shaped nuclei were found in groups treated with
100 mg Br/l, and 400 mg Br-/l (133 days). These changes, with previously published light microscopical, radioanalytical and
biochemical findings, confirm the goitrogenic effect of bromide."
Impact of high bromide intake in the rat dam on iodine transfer to the sucklings.
Pavelka S, Babicky A, Lener J, Vobecky M.
Food Chem Toxicol. 2002 Jul;40(7):1041-5.
[abstract only]
A significant impact of high bromide levels in the organism of the mother on iodine transfer to the sucklings was established in
experiments with female Wistar rats. The observed decrease in iodine transfer to the young through mothers' milk and/or an increase
in the bromide concentration in the milk, caused a decrease in body weight of the pups. Enhanced bromide levels also adversely
affected the thyroid gland of the young. High bromide intake in the lactating dams caused a decrease in iodide accumulation in the
mammary glands, and also an increase in iodide elimination through the kidneys.
High bromide intake affects the accumulation of iodide in the rat thyroid and skin.
Pavelka S, Babicky A, Vobecky M, Lener J.
Biol Trace Elem Res. 2001 Summer;82(1-3):133-42.
[abstract only]
"The effect of a high bromide intake on the kinetics of iodide uptake and elimination in the thyroid and skin of adult male rats was
studied. In rats fed a diet with sufficient iodine supply (> 25 microg I/d), the iodide accumulation in the skin predominated during the
first hours after 131I iodide application. From this organ, radioiodide was gradually transferred into the thyroid. A high bromide intake
(> 150 mg Br-/d) in these animals led to a marked decrease in iodide accumulation, especially by the thyroid, because of an increase
in iodide elimination both from the thyroid and from the skin. In rats kept under the conditions of iodine deficiency (< 1 micro I/d), the
iodide accumulation in the thyroid, but not in the skin, was markedly increased as a result of a thyrotropic stimulation. The effect of a
high bromide intake (> 100 mg Br-/d) in these animals was particularly pronounced because the rates of iodide elimination were most
accelerated both from their thyroid and from their skin.
Effect of high bromide levels in the organism on the biological half-life of iodine in the rat.
Pavelka S, Babicky A, Vobecky M, Lener J.
Biol Trace Elem Res. 2001 Summer;82(1-3):125-32.
[abstract only]
In experiments on rats, a significant influence of an extraordinarily high bromide intake on the whole-body biological half-life of
iodine was established. Very high bromide intake (1) decreased the amount of radioiodide accumulated in the thyroid, (2) changed
the proportion between the amount of iodine retained in the thyroid and the total amount of absorbed iodine, (3) significantly
shortened the biological half-life of iodine in the thyroid from approximately 101 h to 33 h in animals maintained on an
iodine-sufficient diet and from 92 h to about 30 h in rats fed a low-iodine diet, and (4) changed the time-course (added a further
phase) of iodine elimination from the body. These changes were caused, with high probability, by an increase of iodine elimination
by kidneys due to an excess of bromide. The overall picture of iodine elimination in animals fed the low-iodine diet was similar to that
in animals maintained on iodine-sufficient diet.
QUENTIN
The Cl-/HCO3- exchanger pendrin in the rat kidney is regulated in response to chronic alterations in chloride balance.
Quentin F, Chambrey R, Trinh-Trang-Tan MM, Fysekidis M, Cambillau M, Paillard M, Aronson PS, Eladari D.
Am J Physiol Renal Physiol. 2004 Dec;287(6):F1179-88. Epub 2004 Aug 3.
Pendrin (Pds; Slc26A4) is a new anion exchanger that is believed to mediate apical Cl(-)/HCO(3)(-) exchange in type B and
non-A-non-B intercalated cells of the connecting tubule and cortical collecting duct. Recently, it has been proposed that this
transporter may be involved in NaCl balance and blood pressure regulation in addition to its participation in the regulation of
acid-base status. The purpose of our study was to determine the regulation of Pds protein abundance during chronic changes in
chloride balance. Rats were subjected to either NaCl, NH(4)Cl, NaHCO(3), KCl, or KHCO(3) loading for 6 days or to a low-NaCl diet or
chronic furosemide administration. Pds protein abundance was estimated by semiquantitative immunoblotting in renal membrane
fractions isolated from the cortex of treated and control rats. We observed a consistent inverse relationship between Pds expression
and diet-induced changes in chloride excretion independent of the administered cation. Conversely, NaCl depletion induced by
furosemide was associated with increased Pds expression. We conclude that Pds expression is specifically regulated in response to
changes in chloride balance
SHIMODA
Preferential renal excretion of iodide derived from thyroxine and triiodothyronine deiodination in man.
Shimoda SI, Kasai K, Kikuchi T, Ieiri T.
J Clin Endocrinol Metab. 1977 Jan;44(1):137-41.
[abstract only]
Tracer doses of 131I- (Carrier free), 131I-T3 and 131-T4 were administered po to 19 healthy male volunteers at intervals 2 to 8 weeks
to study whether or not part of the iodide generated in the kidney from T3 and T4 deiodination may enter the renal tubular lumen and
be excreted in the urine without entering the blood stream. U(urine)/T(thyroid) ratios of the radioactivity from these materials were
employed as the index of the comparison. U/T ratios were severalfold higher 24 h after 131I-T3 or 131I-T4 administration than after
131I-. The data indicate that the 131I- derived from T3 and T4 metabolism is more readily excreted into urine than 131I- which
reaches the kidney as inorganic iodide.
Iodine metabolism: preferential renal excretion of iodide derived from triiodothyronine deiodination.
Shimoda S, Greer MA.
Science. 1972 Mar 17;175(27):1266-7.
[abstract only]
Measurements were made in rats of the relative rates of accumulation in urine or in the thyroid of radioactive iodide derived from
simultaneous injections of 131I-labeled triiodothyronine and 125I-labeled iodide. The data indicate that deiodination of
triiodothyronine by the kidney results in a loss into the urine of iodine which does not enter the general body iodide pool. This renal
"iodide leak" should be considered in kinetic models of iodine metabolism.
SMALLRIDGE
Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression.
Smallridge RC, Castro MR, Morris JC, Young PR, Reynolds JC, Merino MJ, Sarlis NJ.
Thyroid. 2001 Aug;11(8):795-804.
[abstract only]
Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the
kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A
61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After
thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit
was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan
showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral
nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS
immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in
the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2.
In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection
during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract
residual radionuclide activity.
SOLEIMANI
Regulation of the apical Cl-/HCO-3 exchanger pendrin in rat cortical collecting duct in metabolic acidosis.
Petrovic S, Wang Z, Ma L, Soleimani M.
Am J Physiol Renal Physiol. 2003 Jan;284(1):F103-12. Epub 2002 Aug 13.
Pendrin is an apical Cl(-)/OH(-)/HCO(3)(-) exchanger in beta-intercalated cells (beta-ICs) of rat and mouse cortical collecting duct
(CCD). However, little is known about its regulation in acid-base disorders. Here, we examined the regulation of pendrin in metabolic
acidosis, a condition known to decrease HCO(3)(-) secretion in CCD. Rats were subjected to NH(4)Cl loading for 4 days, which resulted
in metabolic acidosis. Apical Cl(-)/HCO(3)(-) exchanger activity in beta-ICs was determined as amplitude and rate of intracellular pH
change when Cl was removed in isolated, microperfused CCDs. Intracellular pH was measured by single-cell digital ratiometric
imaging using fluorescent pH-sensitive dye 2',7'-bis-(3-carboxypropyl)-5-(and-6)-carboxyfluorescein-AM. Pendrin mRNA expression in
kidney cortex was examined by Northern blot hybridizations. Expression of pendrin protein was assessed by indirect
immunofluorescence. Microperfused CCDs isolated from acidotic rats demonstrated approximately 60% reduction in apical
Cl(-)/HCO(3)(-) exchanger activity in beta-ICs (P < 0.001 vs. control). Northern blot hybridizations indicated that the mRNA expression
of pendrin in kidney cortex decreased by 68% in acidotic animals (P < 0.02 vs. control). Immunofluorescence labeling demonstrated
significant reduction in pendrin expression in CCDs of acidotic rats. We conclude that metabolic acidosis decreases the activity of the
apical Cl(-)/HCO(3)(-) exchanger in beta-ICs of the rat CCD by reducing the expression of pendrin. Adaptive downregulation of pendrin
in metabolic acidosis indicates the important role of this exchanger in acid-base regulation in the CCD.
Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex.
Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE.
Am J Physiol Renal Physiol. 2001 Feb;280(2):F356-64.
The identities of the apical Cl-/base exchangers in kidney proximal tubule and cortical collecting duct (CCD) cells remain unknown.
Pendrin (PDS), which is expressed at high levels in the thyroid and its mutation causes Pendred's syndrome, is shown to be an anion
exchanger. We investigated the renal distribution of PDS and its function. Our results demonstrate that pendrin mRNA expression in
the rat kidney is abundant and limited to the cortex. Proximal tubule suspensions isolated from kidney cortex were highly enriched in
pendrin mRNA. Immunoblot analysis studies localized pendrin to cortical brush-border membranes. Nephron segment RT-PCR
localized pendrin mRNA to proximal tubule and CCD. Expression studies in HEK-293 cells demonstrated that pendrin functions in the
Cl-/OH-, Cl-/HCO3-, and Cl-/formate exchange modes. The conclusion is that pendrin is an apical Cl-/base exchanger in the kidney
proximal tubule and CCD and mediates Cl-/OH-, Cl-/HCO3-, and Cl-/formate exchange.
SPITZWEG
Expression of the sodium iodide symporter in human kidney.
Spitzweg C, Dutton CM, Castro MR, Bergert ER, Goellner JR, Heufelder AE, Morris JC.
Kidney Int. 2001 Mar;59(3):1013-23.
BACKGROUND: The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide
in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting
that iodide transport in these tissues is conferred by the expression of functional NIS protein.
METHODS: The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain
reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide
accumulation studies in kidney cells.
RESULTS: Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed
hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full
identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the
presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO)
cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue
using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no
hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by
Western blot analysis. In addition, accumulation of (125)I was detected in human kidney cells in vitro and was shown to be sodium
dependent and sensitive to perchlorate.
CONCLUSIONS: Functional hNIS expression was demonstrated in the renal tubular system, suggesting that renal iodide transport may
be, at least in part, an active process driven by NIS.
We found most prominent hNIS-specific immunoreactivity in the distal tubular system, with lower staining in the proximal tubules and
no hNIS-specific immunostaining in the glomeruli.
Possible functions of trapped and organified iodide in extrathyroidal tissues may include antiproliferative and antioxidative effects, as
demonstrated for certain iodolipids (iodolactones, iodoaldehydes) in the thyroid gland. Interestingly, alpha-iodohexadecanal, a
naturally occurring iodoaldehyde has been shown to inhibit adenylyl cyclase in kidney cortex in a similar fashion to its activity in
thyroid cells.
Iodide is subject to an active secretory process by the renal tubule.
It has been postulated that iodide enters the basolateral aspect of the cell through the Na/K/2Cl cotransporter and exits the cell via
the apical CFTR (cystic fibrosis transmembrane regulator) chloride channel, thereby mediating the active transcellular secretion of
iodide into the cyst lumen.... It is likely that hNIS is responsible for the secretion of I-131 into renal cysts and therefore iodide transport
in the renal tubular system.... NIS protein expression in membrane preparations of human kidney cells, detection of NIS-specific
iodide accumulating activity in human kidney cells..., cytoplasmic NIS-specific immunoreactivity throughout the proximal and distal
tubular system, including collecting ducts and the thick ascending loop of Henle suggest that NIS may mediate transepithelial as well
as intracellular iodide transport in kidney.
Iodide clearance in the kidney varies with thyroid status, being lower in hypothyroidism and increased in hyperthyroidism, which is
mainly explained by parallel changes of glomerular filtration. Given the expression of functional NIS protein in the renal tubular
system, it also may be possible that NIS protein expression or functional NIS activity is regulated in altered thyroid status to adjust
iodide clearance.... Goiter formation, in iodine deficient areas may result, at least in part, from interindividual variability of renal NIS
expression levels.
End-stage renal disease patients have been reported to have a higher frequency of goiter, thyroid nodules, and hypothyroidism.
Primary hypothyroidism occurs in up to 9.5% of end-stage renal disease patients compared with 0.6 to 1/1% of the general
population, with elevated antimicrosomal antibody titers in about 50%, suggesting an underlying autoimmune mechanism.
hNIS, which has been identified as a new potential autoantigen in the pathogenesis of autoimmune thyroid disease, may become a
target antigen for cross-reacting T cells and autoantibodies during the evolution of chronic renal disease, thereby eliciting an
autoimmune process in the thyroid gland.
Kidney pg 3
PAVELKA, BABICKY, VOBECKY
Biological half-life of bromide in the rat depends primarily on the magnitude of sodium intake.
Pavelka S, Babicky A, Vobecky M.
Physiol Res. 2005;54(6):639-44.
The parallel course of the excretion rates of bromide and sodium ions was demonstrated in adult male and female rats administered
simultaneously with potassium 82Br-bromide and 24Na-sodium chloride. The animals were exposed to various intakes of sodium ions
accompanied with five different anions: Br-, Cl-, HCO3-, ClO4-, and SCN-. Regardless of the anion accompanying the sodium ion, the
excretion rates of 82Br- and 24Na+ ions were proportional to the magnitude of sodium intake in the animals. Hence, we have proved
our hypothesis that the biological half-life of bromide depends on the magnitude of sodium intake rather than on the intake of chlorid
Biological half-lives of bromide and sodium in the rat are connected and dependent on the physiological state.
Babicky A, Pavelka S, Vobecky M.
Biol Trace Elem Res. 2005 Jan;103(1):49-58.
[abstract only]
The parallel course of the excretion rates of sodium and bromide ions was demonstrated in adult male rats administered
simultaneously with 24Na-sodium chloride and 82Br-bromide. These excretion rates were inversely proportional to the magnitude of
sodium intake in the animals. The biological half-life of bromide, as a substitute for sodium or chloride, was investigated with the aid
of the radionuclide 82Br in animals situated in very different physiological states (i.e., in lactating and nonlactating female rats as
well as in young rats of varying ages [2, 4, 6, and 10 wk of age]). The 82Br radioactivity retained in mothers and in whole litters was
measured in vivo at appropriate time intervals (up to 240 h) after the application of 82Br-bromide to the mothers. The time-course of
the changes in the 82Br radioactivity of the young was calculated as the difference between the rate of 82Br intake in the mother's
milk and the 82Br excretion through the kidneys into the urine. The rate of 82Br excretion through the kidneys of the dam could be
calculated also. Nonweaned young rats (12 d) had the highest half-life (269 h) and lactating dams had the lowest (44 h). The
determined values demonstrated that nonweaned young apparently conserve sodium, because of its relatively low concentration in
mother's milk, whereas lactating dams, because of their large food intake, waste sodium.
Metabolism of bromide and its interference with the metabolism of iodine.
Pavelka S.
Physiol Res. 2004;53 Suppl 1:S81-90. Review.
The present knowledge about the metabolism of bromide with respect to its goitrogenic effects, including some conclusions drawn
from our recent research on this subject, is reviewed. Firstly, the biological behavior of bromide ion is compared with that of chloride
and iodide. Secondly, the details about distribution and kinetics of bromide ions in the body and in 15 different organs and tissues of
the rat are given. Significant correlation between the values of the steady-state concentration of bromide in the respective tissue and
of the corresponding biological half-life was found in most tissues examined. A remarkably high concentration of radiobromide was
found in the skin, which represents, due to its large mass, the most abundant depot of bromide in the body of the rat. Thirdly, the
effects of excessive bromide on the rat thyroid are summarized, along with the interference of exogenous bromide with the
whole-body metabolism of iodine. It is suggested that high levels of bromide in the organism of experimental animals can influence
their iodine metabolism in two parallel ways: by a decrease in iodide accumulation in the thyroid and skin (and in the mammary
glands in lactating dams), and by a rise in iodide excretion by kidneys. By accelerating the renal excretion of iodide, excessive
bromide can also influence the pool of exchangeable iodide in the thyroid. Finally, our recent results concerning the influence of
high bromide intake in the lactating rat dam on iodine and bromide transfer to the suckling, and the impact of seriously decreased
iodine content and increased bromide concentration in mother's milk on the young are discussed. We must state, however, that the
virtue of the toxic effects of excessive bromide on the thyroid gland and its interference with the biosynthesis of thyroid hormones, as
well as the exact mechanism of bromide interference with postnatal developmental processes remains to be elucidated.
Biological half-lives of bromide and sodium in the rat are connected and dependent on the physiological state.
Babicky A, Pavelka S, Vobecky M.
Biol Trace Elem Res. 2005 Jan;103(1):49-58.
[abstract only]
The parallel course of the excretion rates of sodium and bromide ions was demonstrated in adult male rats administered
simultaneously with 24Na-sodium chloride and 82Br-bromide. These excretion rates were inversely proportional to the magnitude of
sodium intake in the animals. The biological half-life of bromide, as a substitute for sodium or chloride, was investigated with the aid
of the radionuclide 82Br in animals situated in very different physiological states (i.e., in lactating and nonlactating female rats as
well as in young rats of varying ages [2, 4, 6, and 10 wk of age]). The 82Br radioactivity retained in mothers and in whole litters was
measured in vivo at appropriate time intervals (up to 240 h) after the application of 82Br-bromide to the mothers. The time-course of
the changes in the 82Br radioactivity of the young was calculated as the difference between the rate of 82Br intake in the mother's
milk and the 82Br excretion through the kidneys into the urine. The rate of 82Br excretion through the kidneys of the dam could be
calculated also. Nonweaned young rats (12 d) had the highest half-life (269 h) and lactating dams had the lowest (44 h). The
determined values demonstrated that nonweaned young apparently conserve sodium, because of its relatively low concentration in
mother's milk, whereas lactating dams, because of their large food intake, waste sodium.
Metabolism of bromide and its interference with the metabolism of iodine.
Pavelka S.
Physiol Res. 2004;53 Suppl 1:S81-90. Review.
The present knowledge about the metabolism of bromide with respect to its goitrogenic effects, including some conclusions drawn
from our recent research on this subject, is reviewed. Firstly, the biological behavior of bromide ion is compared with that of chloride
and iodide. Secondly, the details about distribution and kinetics of bromide ions in the body and in 15 different organs and tissues of
the rat are given. Significant correlation between the values of the steady-state concentration of bromide in the respective tissue and
of the corresponding biological half-life was found in most tissues examined. A remarkably high concentration of radiobromide was
found in the skin, which represents, due to its large mass, the most abundant depot of bromide in the body of the rat. Thirdly, the
effects of excessive bromide on the rat thyroid are summarized, along with the interference of exogenous bromide with the
whole-body metabolism of iodine. It is suggested that high levels of bromide in the organism of experimental animals can influence
their iodine metabolism in two parallel ways: by a decrease in iodide accumulation in the thyroid and skin (and in the mammary
glands in lactating dams), and by a rise in iodide excretion by kidneys. By accelerating the renal excretion of iodide, excessive
bromide can also influence the pool of exchangeable iodide in the thyroid. Finally, our recent results concerning the influence of
high bromide intake in the lactating rat dam on iodine and bromide transfer to the suckling, and the impact of seriously decreased
iodine content and increased bromide concentration in mother's milk on the young are discussed. We must state, however, that the
virtue of the toxic effects of excessive bromide on the thyroid gland and its interference with the biosynthesis of thyroid hormones, as
well as the exact mechanism of bromide interference with postnatal developmental processes remains to be elucidated.
The effect of bromide on the ultrastructure of rat thyrocytes.
Velicky J, Titlbach M, Lojda Z, Duskova J, Vobecky M, Raska I.
Ann Anat. 2004 Jun;186(3):209-16.
[abstract only]
"Electron microscopic examination of thyroid tissue following administration of bromide to rats showed marked hypertrophy and
hyperplasia in the thyrocytes, microfollicular rearrangement and lowered volume of colloid. The luminal surface of the thyrocytes
showed increased size and number of microvilli, often filling the microlumen. Most of the nuclei were irregular in shape with unusual
incisions and a higher density of chromatin. Proliferation of ER was seen with significantly dilated cisterns containing low electron
density material. The Golgi complex was well developed and larger in rats receiving 10 mg Br/l drinking water (16 days) and 100 mg
Br/l (16 and 66 days) than in control rats. Granules and small spherical structures (50-100 nm) appeared in the subapical part of the
cytoplasm and their number increased in animals after administration of 50 mg Br-/l (16 and 66 days), 100 mg Br-/l (16 and 66 days),
200 and 400 mg Br-/l (133 days). In contrast, their number was reduced in thyrocytes of rats treated with 100 mg Br/l (16, 66 and 133
days). Colloid droplets were only rarely found. There was no significant change in the amount of mitochondria, secondary lysosomes
including phagolysosomes. Some thyrocytes showed signs of necrosis in animals following administration of 10 mg Br/l (16 days, 100
and 400 mg Br/l, 133 days). Clusters of thyrocytes with spongy cytoplasm and bizarre shaped nuclei were found in groups treated with
100 mg Br/l, and 400 mg Br-/l (133 days). These changes, with previously published light microscopical, radioanalytical and
biochemical findings, confirm the goitrogenic effect of bromide."
Impact of high bromide intake in the rat dam on iodine transfer to the sucklings.
Pavelka S, Babicky A, Lener J, Vobecky M.
Food Chem Toxicol. 2002 Jul;40(7):1041-5.
[abstract only]
A significant impact of high bromide levels in the organism of the mother on iodine transfer to the sucklings was established in
experiments with female Wistar rats. The observed decrease in iodine transfer to the young through mothers' milk and/or an increase
in the bromide concentration in the milk, caused a decrease in body weight of the pups. Enhanced bromide levels also adversely
affected the thyroid gland of the young. High bromide intake in the lactating dams caused a decrease in iodide accumulation in the
mammary glands, and also an increase in iodide elimination through the kidneys.
High bromide intake affects the accumulation of iodide in the rat thyroid and skin.
Pavelka S, Babicky A, Vobecky M, Lener J.
Biol Trace Elem Res. 2001 Summer;82(1-3):133-42.
[abstract only]
"The effect of a high bromide intake on the kinetics of iodide uptake and elimination in the thyroid and skin of adult male rats was
studied. In rats fed a diet with sufficient iodine supply (> 25 microg I/d), the iodide accumulation in the skin predominated during the
first hours after 131I iodide application. From this organ, radioiodide was gradually transferred into the thyroid. A high bromide intake
(> 150 mg Br-/d) in these animals led to a marked decrease in iodide accumulation, especially by the thyroid, because of an increase
in iodide elimination both from the thyroid and from the skin. In rats kept under the conditions of iodine deficiency (< 1 micro I/d), the
iodide accumulation in the thyroid, but not in the skin, was markedly increased as a result of a thyrotropic stimulation. The effect of a
high bromide intake (> 100 mg Br-/d) in these animals was particularly pronounced because the rates of iodide elimination were most
accelerated both from their thyroid and from their skin.
Effect of high bromide levels in the organism on the biological half-life of iodine in the rat.
Pavelka S, Babicky A, Vobecky M, Lener J.
Biol Trace Elem Res. 2001 Summer;82(1-3):125-32.
[abstract only]
In experiments on rats, a significant influence of an extraordinarily high bromide intake on the whole-body biological half-life of
iodine was established. Very high bromide intake (1) decreased the amount of radioiodide accumulated in the thyroid, (2) changed
the proportion between the amount of iodine retained in the thyroid and the total amount of absorbed iodine, (3) significantly
shortened the biological half-life of iodine in the thyroid from approximately 101 h to 33 h in animals maintained on an
iodine-sufficient diet and from 92 h to about 30 h in rats fed a low-iodine diet, and (4) changed the time-course (added a further
phase) of iodine elimination from the body. These changes were caused, with high probability, by an increase of iodine elimination
by kidneys due to an excess of bromide. The overall picture of iodine elimination in animals fed the low-iodine diet was similar to that
in animals maintained on iodine-sufficient diet.
QUENTIN
The Cl-/HCO3- exchanger pendrin in the rat kidney is regulated in response to chronic alterations in chloride balance.
Quentin F, Chambrey R, Trinh-Trang-Tan MM, Fysekidis M, Cambillau M, Paillard M, Aronson PS, Eladari D.
Am J Physiol Renal Physiol. 2004 Dec;287(6):F1179-88. Epub 2004 Aug 3.
Pendrin (Pds; Slc26A4) is a new anion exchanger that is believed to mediate apical Cl(-)/HCO(3)(-) exchange in type B and
non-A-non-B intercalated cells of the connecting tubule and cortical collecting duct. Recently, it has been proposed that this
transporter may be involved in NaCl balance and blood pressure regulation in addition to its participation in the regulation of
acid-base status. The purpose of our study was to determine the regulation of Pds protein abundance during chronic changes in
chloride balance. Rats were subjected to either NaCl, NH(4)Cl, NaHCO(3), KCl, or KHCO(3) loading for 6 days or to a low-NaCl diet or
chronic furosemide administration. Pds protein abundance was estimated by semiquantitative immunoblotting in renal membrane
fractions isolated from the cortex of treated and control rats. We observed a consistent inverse relationship between Pds expression
and diet-induced changes in chloride excretion independent of the administered cation. Conversely, NaCl depletion induced by
furosemide was associated with increased Pds expression. We conclude that Pds expression is specifically regulated in response to
changes in chloride balance
SHIMODA
Preferential renal excretion of iodide derived from thyroxine and triiodothyronine deiodination in man.
Shimoda SI, Kasai K, Kikuchi T, Ieiri T.
J Clin Endocrinol Metab. 1977 Jan;44(1):137-41.
[abstract only]
Tracer doses of 131I- (Carrier free), 131I-T3 and 131-T4 were administered po to 19 healthy male volunteers at intervals 2 to 8 weeks
to study whether or not part of the iodide generated in the kidney from T3 and T4 deiodination may enter the renal tubular lumen and
be excreted in the urine without entering the blood stream. U(urine)/T(thyroid) ratios of the radioactivity from these materials were
employed as the index of the comparison. U/T ratios were severalfold higher 24 h after 131I-T3 or 131I-T4 administration than after
131I-. The data indicate that the 131I- derived from T3 and T4 metabolism is more readily excreted into urine than 131I- which
reaches the kidney as inorganic iodide.
Iodine metabolism: preferential renal excretion of iodide derived from triiodothyronine deiodination.
Shimoda S, Greer MA.
Science. 1972 Mar 17;175(27):1266-7.
[abstract only]
Measurements were made in rats of the relative rates of accumulation in urine or in the thyroid of radioactive iodide derived from
simultaneous injections of 131I-labeled triiodothyronine and 125I-labeled iodide. The data indicate that deiodination of
triiodothyronine by the kidney results in a loss into the urine of iodine which does not enter the general body iodide pool. This renal
"iodide leak" should be considered in kinetic models of iodine metabolism.
SMALLRIDGE
Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression.
Smallridge RC, Castro MR, Morris JC, Young PR, Reynolds JC, Merino MJ, Sarlis NJ.
Thyroid. 2001 Aug;11(8):795-804.
[abstract only]
Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the
kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A
61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After
thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit
was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan
showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral
nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS
immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in
the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2.
In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection
during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract
residual radionuclide activity.
SOLEIMANI
Regulation of the apical Cl-/HCO-3 exchanger pendrin in rat cortical collecting duct in metabolic acidosis.
Petrovic S, Wang Z, Ma L, Soleimani M.
Am J Physiol Renal Physiol. 2003 Jan;284(1):F103-12. Epub 2002 Aug 13.
Pendrin is an apical Cl(-)/OH(-)/HCO(3)(-) exchanger in beta-intercalated cells (beta-ICs) of rat and mouse cortical collecting duct
(CCD). However, little is known about its regulation in acid-base disorders. Here, we examined the regulation of pendrin in metabolic
acidosis, a condition known to decrease HCO(3)(-) secretion in CCD. Rats were subjected to NH(4)Cl loading for 4 days, which resulted
in metabolic acidosis. Apical Cl(-)/HCO(3)(-) exchanger activity in beta-ICs was determined as amplitude and rate of intracellular pH
change when Cl was removed in isolated, microperfused CCDs. Intracellular pH was measured by single-cell digital ratiometric
imaging using fluorescent pH-sensitive dye 2',7'-bis-(3-carboxypropyl)-5-(and-6)-carboxyfluorescein-AM. Pendrin mRNA expression in
kidney cortex was examined by Northern blot hybridizations. Expression of pendrin protein was assessed by indirect
immunofluorescence. Microperfused CCDs isolated from acidotic rats demonstrated approximately 60% reduction in apical
Cl(-)/HCO(3)(-) exchanger activity in beta-ICs (P < 0.001 vs. control). Northern blot hybridizations indicated that the mRNA expression
of pendrin in kidney cortex decreased by 68% in acidotic animals (P < 0.02 vs. control). Immunofluorescence labeling demonstrated
significant reduction in pendrin expression in CCDs of acidotic rats. We conclude that metabolic acidosis decreases the activity of the
apical Cl(-)/HCO(3)(-) exchanger in beta-ICs of the rat CCD by reducing the expression of pendrin. Adaptive downregulation of pendrin
in metabolic acidosis indicates the important role of this exchanger in acid-base regulation in the CCD.
Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex.
Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE.
Am J Physiol Renal Physiol. 2001 Feb;280(2):F356-64.
The identities of the apical Cl-/base exchangers in kidney proximal tubule and cortical collecting duct (CCD) cells remain unknown.
Pendrin (PDS), which is expressed at high levels in the thyroid and its mutation causes Pendred's syndrome, is shown to be an anion
exchanger. We investigated the renal distribution of PDS and its function. Our results demonstrate that pendrin mRNA expression in
the rat kidney is abundant and limited to the cortex. Proximal tubule suspensions isolated from kidney cortex were highly enriched in
pendrin mRNA. Immunoblot analysis studies localized pendrin to cortical brush-border membranes. Nephron segment RT-PCR
localized pendrin mRNA to proximal tubule and CCD. Expression studies in HEK-293 cells demonstrated that pendrin functions in the
Cl-/OH-, Cl-/HCO3-, and Cl-/formate exchange modes. The conclusion is that pendrin is an apical Cl-/base exchanger in the kidney
proximal tubule and CCD and mediates Cl-/OH-, Cl-/HCO3-, and Cl-/formate exchange.
SPITZWEG
Expression of the sodium iodide symporter in human kidney.
Spitzweg C, Dutton CM, Castro MR, Bergert ER, Goellner JR, Heufelder AE, Morris JC.
Kidney Int. 2001 Mar;59(3):1013-23.
BACKGROUND: The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide
in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting
that iodide transport in these tissues is conferred by the expression of functional NIS protein.
METHODS: The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain
reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide
accumulation studies in kidney cells.
RESULTS: Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed
hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full
identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the
presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO)
cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue
using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no
hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by
Western blot analysis. In addition, accumulation of (125)I was detected in human kidney cells in vitro and was shown to be sodium
dependent and sensitive to perchlorate.
CONCLUSIONS: Functional hNIS expression was demonstrated in the renal tubular system, suggesting that renal iodide transport may
be, at least in part, an active process driven by NIS.
We found most prominent hNIS-specific immunoreactivity in the distal tubular system, with lower staining in the proximal tubules and
no hNIS-specific immunostaining in the glomeruli.
Possible functions of trapped and organified iodide in extrathyroidal tissues may include antiproliferative and antioxidative effects, as
demonstrated for certain iodolipids (iodolactones, iodoaldehydes) in the thyroid gland. Interestingly, alpha-iodohexadecanal, a
naturally occurring iodoaldehyde has been shown to inhibit adenylyl cyclase in kidney cortex in a similar fashion to its activity in
thyroid cells.
Iodide is subject to an active secretory process by the renal tubule.
It has been postulated that iodide enters the basolateral aspect of the cell through the Na/K/2Cl cotransporter and exits the cell via
the apical CFTR (cystic fibrosis transmembrane regulator) chloride channel, thereby mediating the active transcellular secretion of
iodide into the cyst lumen.... It is likely that hNIS is responsible for the secretion of I-131 into renal cysts and therefore iodide transport
in the renal tubular system.... NIS protein expression in membrane preparations of human kidney cells, detection of NIS-specific
iodide accumulating activity in human kidney cells..., cytoplasmic NIS-specific immunoreactivity throughout the proximal and distal
tubular system, including collecting ducts and the thick ascending loop of Henle suggest that NIS may mediate transepithelial as well
as intracellular iodide transport in kidney.
Iodide clearance in the kidney varies with thyroid status, being lower in hypothyroidism and increased in hyperthyroidism, which is
mainly explained by parallel changes of glomerular filtration. Given the expression of functional NIS protein in the renal tubular
system, it also may be possible that NIS protein expression or functional NIS activity is regulated in altered thyroid status to adjust
iodide clearance.... Goiter formation, in iodine deficient areas may result, at least in part, from interindividual variability of renal NIS
expression levels.
End-stage renal disease patients have been reported to have a higher frequency of goiter, thyroid nodules, and hypothyroidism.
Primary hypothyroidism occurs in up to 9.5% of end-stage renal disease patients compared with 0.6 to 1/1% of the general
population, with elevated antimicrosomal antibody titers in about 50%, suggesting an underlying autoimmune mechanism.
hNIS, which has been identified as a new potential autoantigen in the pathogenesis of autoimmune thyroid disease, may become a
target antigen for cross-reacting T cells and autoantibodies during the evolution of chronic renal disease, thereby eliciting an
autoimmune process in the thyroid gland.