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Kidney pg 3
VADSTRUP
Comparative aspects of iodine conservation in mammals.
Vadstrup S.
Comp Biochem Physiol Comp Physiol. 1993 Sep;106(1):15-7. Review.
1. Comparative aspects of iodine conservation in mammals were studied on the basis of published data on kidney and thyroid weights
and function.
2. Very small mammals possessed an efficient reabsorption of iodide to compensate for the high glomerular filtration rate (GFR).
3. Humans and mammals of a similar and larger size had "lost" the ability to reabsorb iodide efficiently.
4. Very large mammals are protected against renal loss of iodide due to the relatively low GFR.
5. Thyroid weights in relation to body weight were highest in humans suggesting that humans and other mammals of a similar size are
especially susceptible to iodine deficiency.
Renal iodide clearance in rabbits.
Vadstrup S.
Acta Endocrinol (Copenh). 1989 Aug;121(2):246-50.
[abstract only]
The purpose of the study was to compare indirect clearance methods based on plasma values and external detection of activity using
small skin attached radioactivity detectors with a direct clearance method based on constant infusion and urine collection. The
experiments were performed in anesthetized rabbits. The plasma iodide concentration was increased 100 times to prevent thyroid
organification of radioactive iodide. [131I]iodide was infused at a constant rate and [125I]iodide was administered iv as a bolus for
indirect clearance determination. The ratio between plasma values and external values 125I-activity was constant in all experiments
from 15 min after administration of [125I]iodide and throughout the experiment. The results of 7 experiments in 3 rabbits showed a
highly significant correlation (r = 0.98) between direct and indirect values within the range of direct clearance values obtained
(0.002-0.6 ml.min-1.kg-1. The direct and indirect clearances were measured simultaneously during a 2-h period of steady state. The
95% confidence interval of the mean ratio between direct and indirect clearances was +/- 20% for plasma activity and +/- 26% for
externally measured activity. It is concluded that both methods of indirect clearance determination can be applied to rabbits to
estimate absolute values of the renal iodide clearance.
A comparison of the effect of TSH, GH and prolactin on the renal iodide excretion in unrestrained rabbits.
Vadstrup S
Acta Endocrinol (Copenh). 1977 Jul;85(3):488-96.
[abstract only]
The immediate effect of graded iv doses of heterologous TSH, GH and prolactin on the renal iodide excretion was sutdied in
unrestrained rabbits with implanted Geiger Muller detectors. Both TSH and GH lowered the fractional excretion rate of iodide. The
duration of the effect was significantly correlated to the magnitude of the administered dose. The lowest dose with a significant effect
was 10-20 mU TSH and 50 mU GH. Prolactin had no similar effect even in high pharmacological doses. An effect similar to that of
small TSH doses was recorded following administration of 20-40 microng TRH iv. The immediate effect of GH on the iodide excretion
accords with previous reports about similar effect on sodium excretion and suggests, that the effect of GH and TSH on the iodide
excretion is secondary to a general effect on kidney function. The demonstration, that the effect is present in unrestrained animals
after administration of physiological doses indicates, that the effect is not only of pharmacological significance, but may also have
physiological significance.
The immediate effect of TSH on renal iodide excretion rate in rabbits.
Vadstrup S, Bojsen J.
Acta Endocrinol (Copenh). 1976 Apr;81(4):723-8.
The renal iodide excretion rate was determined in unrestrained female rabbits by means of conventional clearance technique or
continuous monitoring of the whole body disappearance of iv injected 125I-iodide using an implanted Geiger-Muller detector. The
immediate effect of pharmacological doses of bovine TSH was studied by both methods and a significant decrease in iodide
excretion rate was recorded following the administration of a single TSH dose of 4 IU. The effect of TSH lasted 3-6 h. Injection of
10-20 mug TRH caused a transient delay in iodide disappearance (30-50 min) while 2-20 mug triiodothyronine iv or sc had no
immediate effect on the iodide disappearance.
The diurnal variation in renal iodide excretion rate in rabbits.
Vadstrup S, Bojsen J.
Acta Endocrinol (Copenh). 1976 Apr;81(4):716-22.
[abstract only]
The diurnal variation in renal iodide excretion rate was determined in unrestrained female rabbits by means of either a conventional
clearance technique or a continuous monitoring of the whole body disappearance of iv injected 125I-iodide using an implanted
Geiger-Muller detector. A distinct diurnal rhythm was detected in the disappearance rate of 125I-iodide. A slow disappearance rate
occurred from 12 p.m. to 6 a.m. (darkness from 5 p.m. to 5 a.m.). The values of iodide excretion rate obtained by both methods were
consistent like in humans with an excretion fraction of 0.3 for iodide in rabbits. In rabbits weighing 3-4 kg the renal iodide excretion
rates were 5-7 ml/min during the rapid phase and 3-4 ml/min during the slow phase.
VARGAS
Vascular and renal function in experimental thyroid disorders.
Vargas F, Moreno JM, Rodriguez-Gomez I, Wangensteen R, Osuna A, Alvarez-Guerra M, Garcia-Estan J.
Eur J Endocrinol. 2006 Feb;154(2):197-212. Review.
This review focuses on the effects of thyroid hormones in vascular and renal systems. Special emphasis is given to the mechanisms by
which thyroid hormones affect the regulation of body fluids, vascular resistance and, ultimately, blood pressure. Vascular function is
markedly affected by thyroid hormones that produce changes in vascular reactivity and endothelial function in hyper- and
hypothyroidism. The hypothyroid state is accompanied by a marked decrease in sensitivity to vasoconstrictors, especially to
sympathetic agonists, alteration that may play a role in the reduced blood pressure of hypothyroid rats, as well as in the preventive
effects of hypothyroidism on experimental hypertension. Moreover, in hypothyroid rats, the endothelium-dependent and nitric oxide
donors vasodilation is reduced. Conversely, the vessels from hyperthyroid rats showed an increased endothelium-dependent
responsiveness that may be secondary to the shear-stress induced by the hyperdynamic circulation, and that may contribute to the
reduced vascular resistance characteristic of this disease. Thyroid hormones also have important effects in the kidney, affecting
renal growth, renal haemodynamics, and salt and water metabolism. In hyperthyroidism, there is a resetting of the
pressure-natriuresis relationship related to hyperactivity of the renin-angiotensin system, which contributes to the arterial
hypertension associated with this endocrine disease. Moreover, thyroid hormones affect the development and/or maintenance of
various forms of arterial hypertension. This review also describes recent advances in our understanding of thyroid hormone action on
nitric oxide and oxidative stress in the regulation of cardiovascular and renal function and in the long-term control of blood pressure.
WAGNER
The emerging role of pendrin in renal chloride reabsorption.
Wagner CA.
Am J Physiol Renal Physiol. 2007 Mar;292(3):F912-3. Epub 2006 Dec 12.
The establishment of pendrin as a pathway for transcellular chloride absorption in the connecting tubule and cortical collecting
segment certainly emphasizes the role of intercalated cells not only in acid-base transport but also in the control of electrolyte
homeostasis and ultimately blood pressure.
Many questions remain open: what is the relative importance of pendrin as transcellular transport pathway in relation to paracellular
pathways under various conditions; how are pendrin abundance and activity regulated and coordinated with ENaC activity; what is
the chloride sensor that mediates pendrin upregulation during chloride depletion; and is pendrin involved in the development of
hypertension?
Regulation of the expression of the Cl-/anion exchanger pendrin in mouse kidney by acid-base status.
Wagner CA, Finberg KE, Stehberger PA, Lifton RP, Giebisch GH, Aronson PS, Geibel JP.
Kidney Int. 2002 Dec;62(6):2109-17.
BACKGROUND: Pendrin belongs to a superfamily of Cl-/anion exchangers and is expressed in the inner ear, the thyroid gland, and
the kidney. In humans, mutations in pendrin cause Pendred syndrome characterized by sensorineural deafness and goiter. Recently
pendrin has been localized to the apical side of non-type A intercalated cells of the cortical collecting duct, and reduced
bicarbonate secretion was demonstrated in a pendrin knockout mouse model. To investigate a possible role of pendrin in modulating
acid-base transport in the cortical collecting duct, we examined the regulation of expression of pendrin by acid-base status in mouse
kidney.
METHODS: Mice were treated orally either with an acid or bicarbonate load (0.28 mol/L NH4Cl or NaHCO3) or received a
K+-deficient diet for one week. Immunohistochemistry and Western blotting was performed.
RESULTS: Acid-loading caused a reduction in pendrin protein expression levels within one day and decreased expression to 23% of
control levels after one week. Concomitantly, pendrin protein was shifted from the apical membrane to the cytosol, and the relative
abundance of pendrin positive cells declined. Similarly, in chronic K+-depletion, known to elicit a metabolic alkalosis, pendrin
protein levels decreased and pendrin expression was shifted to an intracellular pool with the relative number of pendrin positive cells
reduced. In contrast, following oral bicarbonate loading pendrin was found exclusively in the apical membrane and the relative
number of pendrin positive cells increased.
CONCLUSIONS: These results are in agreement with a potential role of pendrin in bicarbonate secretion and regulation of acid-base
transport in the cortical collecting duct.
WALL
Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney: role of pendrin in mineralocorticoid-induced hypertension.
Verlander JW, Hassell KA, Royaux IE, Glapion DM, Wang ME, Everett LA, Green ED, Wall SM.
Hypertension. 2003 Sep;42(3):356-62. Epub 2003 Aug 18.
Pendrin is an anion exchanger expressed along the apical plasma membrane and apical cytoplasmic vesicles of type B and of
non-A, non-B intercalated cells of the distal convoluted tubule, connecting tubule, and cortical collecting duct. Thus, Pds (Slc26a4)
is a candidate gene for the putative apical anion-exchange process of the type B intercalated cell. Because apical anion
exchange-mediated transport is upregulated with deoxycorticosterone pivalate (DOCP), we tested whether Pds mRNA and protein
expression in mouse kidney were upregulated after administration of this aldosterone analogue by using quantitative real-time
polymerase chain reaction as well as light and electron microscopic immunolocalization. In kidneys from DOCP-treated mice, Pds
mRNA increased 60%, whereas pendrin protein expression in the apical plasma membrane increased 2-fold in non-A, non-B
intercalated cells and increased 6-fold in type B cells. Because pendrin transports HCO3- and Cl-, we tested whether DOCP treatment
unmasks abnormalities in acid-base or NaCl balance in Pds (-/-) mice. In the absence of DOCP, arterial pH, systolic blood pressure,
and body weight were similar in Pds (+/+) and Pds (-/-) mice. After DOCP treatment, weight gain and hypertension were observed in
Pds (+/+) but not in Pds (-/-) mice. Moreover, after DOCP administration, metabolic alkalosis was more severe in Pds (-/-) than Pds (+/+)
mice. We conclude that pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of
mineralocorticoid-induced hypertension and metabolic alkalosis.
Localization of pendrin in mouse kidney.
Wall SM, Hassell KA, Royaux IE, Green ED, Chang JY, Shipley GL, Verlander JW.
Am J Physiol Renal Physiol. 2003 Jan;284(1):F229-41. Epub 2002 Aug 27.
Pendrin is an anion exchanger expressed in type B intercalated cells of the cortical collecting duct (CCD). Whether pendrin localizes
to other nephron segments with intercalated cells is unknown. Moreover, whether pendrin is expressed in proximal tubule is debated.
Thus the distribution of pendrin mRNA and protein expression in mouse kidney was investigated by using light and electron
microscopic immunohistochemistry and quantitative real-time PCR. We observed that pendrin mRNA is expressed mainly in cortex.
Within cortex, pendrin mRNA is at least fivefold higher in CCD and the connecting tubule (CNT) than in the other segments. Pendrin
protein was observed in a subset of cells within the distal convoluted tubule as well as in type B and in non-A-non-B intercalated cells
of the CNT and CCD. In type B intercalated cells, pendrin immunoreactivity was highest in apical cytoplasmic vesicles with little
immunolabel along the apical plasma membrane. In non-A-non-B intercalated cells, intense pendrin immunoreactivity was detected
along the apical plasma membrane. These differences in the subcellular distribution of pendrin immunolabel were confirmed by
morphometric analysis. In conclusion, pendrin is expressed in the mouse distal convoluted tubule, CCD, and CNT along the apical
plasma membrane of non-A-non-B intercalated cells and in subapical cytoplasmic vesicles of type B intercalated cells.
XING, SIDRANSKY
Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis.
Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, Sidransky D.
Cancer Res. 2004 Mar 1;64(5):1664-8.
Follicular epithelial cell-derived thyroid tumors are common neoplasms comprised mainly of benign thyroid adenomas, follicular
thyroid cancers, and papillary thyroid cancers (PTCs). Hypermethylation of the tumor suppressor gene RASSF1A and activating
mutation of BRAF gene have been reported recently in thyroid cancers. To additionally investigate the roles of these two
epigenetic/genetic alterations in thyroid tumor progression, we examined their occurrences and relationship in both benign and
malignant thyroid neoplasms. With real-time quantitative methylation-specific PCR, we found that 4 of 9 (44%) benign adenomas, 9
of 12 (75%) follicular thyroid cancers tumors, and 6 of 30 (20%) of PTC tumors harbored promoter methylation in > or = 25% of
RASSF1A alleles. Additional quantitative analysis revealed RASSF1A methylation only in BRAF mutation-negative PTCs. A similar
inverse correlation of RASSF1A methylation with BRAF mutation was seen in thyroid tumor cell lines. Our results, therefore, suggest
that epigenetic inactivation of RASSF1A through aberrant methylation is an early step in thyroid tumorigenesis. Like the previously
reported mutually exclusive relationship between BRAF mutation and other Ras pathway components such as RET/PTC
rearrangement, a mutually exclusive relationship also exists between BRAF mutation and RASSF1A methylation in thyroid
tumorigenesis.
Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis.
Xing M, Tokumaru Y, Wu G, Westra WB, Ladenson PW, Sidransky D.
Cancer Res. 2003 May 1;63(9):2312-5.
Expression of the recently cloned Pendred syndrome gene SLC26A4 or PDS has been found to be decreased or even absent in
various thyroid tumors. To explore the underlying mechanism, we conducted DNA sequencing and methylation-specific PCR studies
in 64 primary thyroid tumors and 6 thyroid cell lines. We found aberrant hypermethylation of the SLC26A4 gene in 44% of
histologically benign adenomas, 46% of follicular thyroid cancers, 71% of papillary thyroid cancers, 71% of anaplastic thyroid
cancers, and 100% of cell lines. A reciprocal relationship between methylation and expression of the gene was confirmed in cell
lines and thyroid tissues. We have thus demonstrated epigenetic changes as a new mechanism in altering the SLC26A4 gene
function, in addition to genetic mutation in Pendred syndrome. SLC26A4 gene methylation in benign adenomas and the relatively
well-differentiated WRO cell line suggest that this alteration is an early event in thyroid tumorigenesis.
Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of
gene silencing.
Xing M, Usadel H, Cohen Y, Tokumaru Y, Guo Z, Westra WB, Tong BC, Tallini G, Udelsman R, Califano JA, Ladenson PW, Sidransky
D.
Cancer Res. 2003 May 1;63(9):2316-21.
Thyroid-stimulating hormone receptor (TSHR) expression is frequently silenced in epithelial thyroid cancers associated with
decreased or absent TSH-promoted iodine uptake. To study the underlying molecular mechanism of decreased TSHR expression, we
examined the methylation status of the TSHR gene promoter by sequencing bisulfite-treated DNA from thyroid tumors. After
identification of methylated sites by sequencing bisulfite-treated DNA, we used methylation-specific polymerase chain reaction and
found frequent CpG methylation in papillary thyroid cancer (23 of 39 patients; 59%) and follicular thyroid cancers (7 of 15 patients;
47%). In contrast, we saw no methylation in normal thyroid tissues and benign adenomas (0 of 8 patients; 0%). In human thyroid tumor
cell lines, we observed that TSHR was normally expressed at the protein and mRNA level in cells where the TSHR gene was
unmethylated, whereas it was silenced in cell lines where the TSHR promoter was hypermethylated. Treatment of the latter cells with
a demethylating agent partially restored TSHR expression. We thus demonstrate aberrant methylation of human TSHR as a likely
molecular pathway responsible for the silencing of this gene in thyroid cancers. We propose that methylation of TSHR may provide a
novel diagnostic marker of malignancy and a basis for potential use of demethylating agents in conjunction with TSH-promoted
radioiodine therapy for epithelial thyroid cancers.
ZAICHICK
Trace elements and thyroid cancer.
Zaichick VY, Tsyb AF, Vtyurin BM.
Analyst. 1995 Mar;120(3):817-21.
To evaluate the importance of trace amounts of elements in thyroid cancer etiology and diagnostics, instrumental neutron activation
analysis has been used to estimate Ag, Co, Cr, Fe, Hg, I, Rb, Sb, Sc, Se, and Zn concentrations in malignant and benign thyroid
nodules as well as in apparently intact paranodular thyroid tissue. Resected material from 135 patients was obtained from operations.
Forty-five cancer cases were diagnosed and the rest were of benign nodules. The thyroid glands of 65 people, 53 male and 12
female, who died and unexpected death or committed suicide, were used as a control group. Trace element contents of the
International Atomic Energy Agency reference material H-4 (animal muscle) were analysed simultaneously with the thyroid tissue in
order to evaluate the accuracy of the obtained data. No dependence of trace element contents on sex and age (14-80 years) was
found for normal thyroids. In paranodular tissue, the Ag, Co, Hg, I and Rb contents were much higher for malignant and benign
nodules than they were for the standard. There was also a slight deficiency of Se in the nodules compared with the standard. This
result supports the hypothesis that the direct toxic heavy metal influence on thyrocytes plays a major role in thyroid cancer etiology,
provided that an adequate level of the defence mechanisms is absent. Iodine concentrations are 15 times lower, on average, in
malignant compared with benign nodules. It is also shown that the radio between the iodine concentration in nodular and
paranodular tissue can be used for in vivo thyroid cancer diagnostics.