Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The type 1 and type 2 isoforms of human 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) play a crucial role, respectively, in modulating glucocorticoid and mineralocorticoid hormone action. Deficiency of the 11 beta-HSD2 isoform, as described in the syndrome of apparent mineralocorticoid excess and following liquorice (glycyrrhetinic acid) or carbenoxolone ingestion, results in hypertension in which cortisol acts as a potent mineralocorticoid. Several studies have addressed the effects of progesterone, glycyrrhetinic acid, and their derivatives on 11 beta-HSD activity, but these were largely undertaken before the characterization of the 11 beta-HSD isoforms. The aim of this study was to evaluate the localization of 11 beta-HSD2 in human kidney and to study the effects of progesterone, glycyrrhetinic acid, and their related compounds on stable transfectants of the human 11 beta-HSD isoforms. Using an in-house sheep antibody against human 11 beta-HSD2, immunoperoxidase studies localized 11 beta-HSD2 to renal cortical and medullary collecting ducts. Glomeruli, vascular structures, loops of Henle, and proximal tubules were all negative. Confocal laser microscopy studies indicated both a cytoplasmic and nuclear localization for the enzyme within renal collecting ducts. The nuclear staining, which was intranuclear and was not associated with the nuclear membrane, accounted for 40% of the total cellular 11 beta-HSD2 immunoreactivity. Kinetic analysis of 11 beta-HSD activity in fetal kidney 293 cells stably transfected with h11 beta-HSD1/pcDNA3 or 11 beta-HSD2/pCR3, indicated, respectively, low-affinity dehydrogenase/oxoreductase activity (Km for F, 1.8 microM; Km for E, 270 nM) and high-affinity dehydrogenase activity (Km for F, 190 nM). The reductase activity of 11 beta-HSD1 was inhibited by 11 alpha-hydroxyprogesterone > carbenoxolone = glycyrrhetinic acid = progesterone > 11 beta-hydroxyprogesterone. The dehydrogenase activity of 11 beta-HSD2 was inhibited 11 alpha-hydroxyprogesterone = 11 beta-hydroxyprogesterone > glycyrrhetinic acid > carbenoxolone = progesterone. 11 beta-HSD2, expressed in the renal collecting duct, serves to protect the mineralocorticoid receptor (MR) in an autocrine fashion. The demonstration of a nuclear localization for what was thought to be principally a microsomal enzyme suggests that interaction between the MR and its ligand (either aldosterone or cortisol) may be a nuclear rather than a cytoplasmic event. The inhibitory effects of progesterone, glycyrrhetinic acid, and related compounds on 11 beta-HSD1 and 2 were similar, and it remains to be seen what implication these findings have for 11 beta-HSD1 action in tissues such as the liver and gonad and renal 11 beta-HSD2 activity in relation to sodium homeostasis and blood pressure control.
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PMID:Human 11 beta-hydroxysteroid dehydrogenase: studies on the stably transfected isoforms and localization of the type 2 isozyme within renal tissue. 902 19

Arginine vasopressin (AVP) and corticosteroid hormones are involved in sodium reabsorption regulation in the renal collecting duct. Synergy between AVP and aldosterone has been well documented, although its mechanism remains unclear. Both aldosterone and glucocorticoid hormones bind to the mineralocorticoid receptor (MR), and mineralocorticoid selectivity depends on the MR-protecting enzyme 11 beta hydroxysteroid deshydrogenase (11-HSD), which metabolizes glucocorticoids into derivatives with low affinity for MR. We have investigated whether the activity of 11-HSD could be influenced by AVP and corticosteroid hormones. This study shows that in isolated rat renal collecting ducts, AVP increases 11-HSD catalytic activity. This effect is maximal at 10(-8) M AVP (a concentration clearly above the normal physiological range of AVP concentrations) and involves the V2 receptor pathway, while activation of protein kinase C or changes in intracellular calcium are ineffective. The stimulatory effect of AVP on 11-HSD is largely reduced after adrenalectomy, and is selectively restored by infusion of aldosterone, not glucocorticoids. We conclude that this synergy between AVP and aldosterone in controlling the activity of 11-HSD is likely to play a pivotal role in resetting mineralocorticoid selectivity, and hence sodium reabsorption capacities of the renal collecting duct.
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PMID:Vasopressin potentiates mineralocorticoid selectivity by stimulating 11 beta hydroxysteroid deshydrogenase in rat collecting duct. 936 57

A6 cells, derived from Xenopus laevis renal tubule, form a high-resistance ion-transporting monolayer when grown on permeable supports and can generate a short-circuit current (SCC) that is stimulated by high levels of the mineralocorticoid aldosterone. Surprisingly, A6 SCC is more responsive to glucocorticoids than to mineralocorticoids, suggesting the possibility that these cells do not contain transcriptionally active mineralocorticoid receptor (MR) and that glucocorticoid receptor (GR) mediates MR-like responses in these collecting duct-like cells. We have examined the response of both SCC and a transfected reporter gene to mineralocorticoids and glucocorticoids in the presence and absence of transfected rat MR (rMR). We found that, in the absence of transfected MR, a reporter gene that can be activated by MR or GR was more responsive to glucocorticoids such as dexamethasone and RU-28362 than to mineralocorticoids such as aldosterone. Transfected rMR underwent mineralocorticoid-dependent nuclear localization and restored both transcriptional sensitivity of a reporter gene and SCC response to mineralocorticoids. These data demonstrate that A6 cells contain transcriptionally active GR but not MR and thus suggest a molecular basis for the defect in A6 cell SCC response to aldosterone. Our results also demonstrate that GR is capable of mediating hormone stimulation of SCC, a classic mineralocorticoid response. Finally, the observation that heterologous expression of rMR can localize normally to the A6 nucleus in a hormone-dependent fashion and restore both the transcriptional and SCC response to mineralocorticoids suggests that MR function is conserved in species as distantly related as toads and mammals.
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PMID:Aldosterone responsiveness of A6 cells is restored by cloned rat mineralocorticoid receptor. 945 10

Recently, we reported that primary cultures of inner medullary collecting duct cells from Dahl salt-sensitive (S) rats absorb more Na+ than do cells cultured from Dahl salt-resistant (R) rats. To begin to evaluate the molecular basis for this difference, we selected four candidate gene products that on the basis of their physiology and genetics could participate in regulation of Na+ transport by these cells. During 24-hour exposure, inhibitors of the cytochrome P450 enzymes had no effect on Na+ transport by either S or R monolayers. Twenty-four-hour exposure to NG-monomethyl-L-arginine (0.5 mmol/L), a nonspecific inhibitor of NO synthase, also had no effect on Na+ transport by either S or R monolayers. Neither atrial natriuretic peptide 1-28 (100 nmol/L) nor 8-Br-cyclic GMP (100 micromol/L) had any short-term effect on Na+ transport by either S or R monolayers. 18-Hydroxy-11-deoxycorticosterone (100 nmol/L), an adrenocorticoid hormone that is produced in greater amounts in S rats, stimulated Na+ transport by both S and R monolayers via the mineralocorticoid receptor; however, its effect was less potent than aldosterone. Congenic rats in which the R isoform of the 11beta-hydroxylase gene was bred onto the S background had monolayers that transported Na+ at a rate similar to the S rats. These results demonstrate that neither cytochrome P450 genes, NO synthase genes, the atrial natriuretic peptide receptor gene, nor the 11beta-hydroxylase gene is a likely candidate to explain the difference in Na+ transport between S and R inner medullary collecting duct monolayers in primary culture.
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PMID:Candidate genes in the regulation of Na+ transport by inner medullary collecting duct cells from Dahl rats. 946 Dec 29

Type 2 11beta-hydroxysteroid dehydrogenase (11betaHSD2) plays a key role in conferring aldosterone selectivity on the mineralocorticoid receptor (MR) by inactivating intracellular glucocorticoids before they can occupy the MR. 11betaHSD2 is a microsomal enzyme expressed in aldosterone target cells, although its subcellular distribution is still unclear. The goal of this study was to determine the subcellular localization of the endogenous 11betaHSD2 in renal aldosterone target cells. We generated an antibody against rabbit 11betaHSD2 and used it in combination with a nuclear marker and confocal laser scanning microscopy. On Western blots the antibody recognized a single band of approximately 41 kDa in the renal cortical collecting duct, outer medullary collecting duct, submandibular gland and adrenal cortex, whereas the colon, liver, renal medulla, and heart were negative. Immunohistochemistry showed specific reaction in the known aldosterone target cells of the kidney (connecting tubule, cortical collecting duct, and outer medullary collecting duct) with no signals over glomeruli, proximal nephron segments, and blood vessels. Staining for 11betaHSD2 was very weak in rabbit colon, and no immunoreactivity could be detected in the heart and brain. Confocal microscopy of kidney sections costained with the 11betaHSD2 antibody and the nuclear marker propidium iodide demonstrated that 11betaHSD2 is in the cytoplasmic compartment with no evidence for nuclear localization. Subcellular localization of 11betaHSD2 to a cytoplasmic compartment seems ideal for fulfilling its biological function, i.e. the efficient inactivation of intracellular glucocorticoids before they occupy MRs, which are predominantly cytoplasmic in the absence of hormone.
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PMID:Extranuclear localization of endogenous 11beta-hydroxysteroid dehydrogenase-2 in aldosterone target cells. 960 6

Mineralocorticoid hormones regulate salt transport along the distal nephron by binding to intracellular receptors and activating gene transcription. Previous experiments showed that systemic aldosterone infusions stimulate thiazide-sensitive Na and Cl transport by distal convoluted tubule (DCT) cells; this effect could have been direct or secondary to systemic hormonal effects. Aldosterone target tissues express both mineralocorticoid receptors and the metabolic enzyme 11beta-hydroxysteroid dehydrogenase type 2. Mineralocorticoid receptors have been localized to the DCT in some experiments, but not in others. Expression of 11beta-hydroxysteroid dehydrogenase type 2 by DCT cells has not been investigated. The present experiments were designed to test the hypothesis that rat DCT cells are targets of aldosterone action. Patterns of mineralocorticoid receptor, 11beta-hydroxysteroid dehydrogenase, thiazide-sensitive Na-Cl cotransporter, and Na/Ca exchanger expression along the distal tubule were examined. A polyclonal antibody was generated to localize the thiazide-sensitive Na-Cl cotransporter. Thiazide-sensitive Na-Cl cotransporter and 11beta-hydroxysteroid dehydrogenase expression were examined using both in situ hybridization and immunocytochemistry; Na/Ca exchanger and mineralocorticoid receptor expression were examined by immunocytochemistry. The results indicate that 11beta-hydroxysteroid dehydrogenase is expressed by DCT cells, as well as connecting tubule cells and principal cells of the collecting duct; expression levels are low near the junction with the thick ascending limb and rise near the transition to the connecting tubule. Mineralocorticoid receptors are expressed by DCT cells, as well as along the thick ascending limb, connecting tubule, and collecting duct. The results indicate that components of the mineralocorticoid receptor system are expressed by DCT cells, suggesting that these cells are targets of aldosterone action.
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PMID:11Beta-hydroxysteroid dehydrogenase, mineralocorticoid receptor, and thiazide-sensitive Na-Cl cotransporter expression by distal tubules. 969 56

11Beta-hydroxysteroid dehydrogenase (11beta-HSD) is thought to confer aldosterone specificity to mineralocorticoid target cells by protecting the mineralocorticoid receptor (MR) from occupancy by endogenous glucocorticoids. In aldosterone target cells the type 2 11beta-HSD is present, which, in contrast to the type 1 11beta-HSD, has very high affinity for its substrate, is unidirectional and prefers NAD as cofactor. cDNAs encoding 11beta-HSD2 have been recently cloned from different species, and the cell-specific expression of its mRNA and protein were determined. 11Beta-HSD2 is expressed in every aldosterone target tissue. Northern analysis revealed that the rabbit 11beta-HSD2 is expressed at high levels in the renal collecting duct and at much lower levels in the colon. RT-PCR experiments demonstrated that 11beta-HSD2 mRNA is present only in aldosterone target cells within the kidney. We determined the subcellular localization of the rabbit 11beta-HSD2 using a chimera encoding 11beta-HSD2 and the green fluorescent protein (GFP). This construct was stably transfected into CHO and MDCK cells. The expressed 11beta-HSD2/GFP protein retained high enzymatic activity, and its characteristics were undistinguishable from those of the native enzyme. The intracellular localization of this protein was determined by fluorescence microscopy. 11Beta-HSD2-associated fluorescence was observed as a reticular network over the cytoplasm whereas the plasma membrane and the nucleus were negative, suggesting endoplasmic reticulum (ER) localization. Co-staining with markers for ER proteins, the Golgi membrane, mitochondria and nucleus confirmed that 11beta-HSD2 is localized exclusively to the ER. To determine what structural motifs are responsible for the ER localization, we generated deletion mutants missing the C-terminal 42 and 118 amino acids, and fused them to GFP. Similarly as with the intact 11beta-HSD2, these mutants localized exclusively to the ER. Both C-terminal deletion mutants completely lost dehydrogenase activity, independently whether activity was determined in intact cells or homogenates. These results indicate that 11beta-HSD2 has a novel ER retrieval signal which is not localized to the C-terminal region. In addition, the C-terminal 118 amino acids are essential for NAD-dependent 11beta-HSD activity.
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PMID:The role of 11beta-hydroxysteroid dehydrogenase in steroid hormone specificity. 969 85

The mammalian distal nephron plays a pivotal role in adjusting urinary sodium excretion. Successive portions of the renal tubule are formed to adapt to this function, and an axial heterogeneity of the distal segments has been defined. The specific transport properties of these epithelia are accomplished by the expression of proteins (cotransporters, exchangers, channels) governing the movement of ions on either cell side. Molecular cloning of these proteins has had a marked impact on the study of their localization and function in the healthy and diseased kidney. Electroneutral cation-chloride cotransporters [Na(K)CC] have been localized to the thick ascending limb and the distal convoluted tubule using specific probes. Proteins implicated in the function of aldosterone target cells, such as the epithelial Na(+) channel (ENaC), the mineralocorticoid receptor (MR) and 11beta-hydroxysteroid dehydrogenase type 2 (11HSD2), an enzyme that confers mineralocorticoid specificity, have been found in the terminal portion of the nephron and the collecting duct. A mineralocorticoid-sensitive component of thiazide-sensitive NaCl transport has been identified in the distal convoluted tubule. Analysis of the ontogeny of these proteins in the maturing kidney has provided a detailed picture of epithelial differentiation and morphological specialization of the renal tubule. The study of mutations of the proteins related with NaCl transport has led to the identification of the molecular causes of inherited human diseases associated with hypo- or hypertension, and the respective sites of an impaired ion transport could be mapped to the renal tubule.
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PMID:Sodium transport-related proteins in the mammalian distal nephron - distribution, ontogeny and functional aspects. 1052 14

The currently available diuretics increase the urinary excretion of sodium chloride by selective inhibition of specific sodium transporters in the loop of Henle and distal nephron. In recent years, the molecular cloning of the distal diuretic-sensitive sodium transporters has improved our understanding of the cellular mechanisms of action of each class of diuretics. The identification of mutations in the genes encoding these transporters in inherited disorders characterized by altered salt balance has provided unequivocal evidence for the roles of the cloned diuretic-sensitive transporters in sodium homeostasis. The biochemical abnormalities observed in these disorders are identical to those induced by the specific diuretic. In the Guibaud-Vainsel syndrome (renal-tubular acidosis with osteopetrosis) the renal disturbances are comparable to the effects of a therapy with acetazolamide. Mutations in the proximal tubular carbonic anhydrase type II are the cause of this rare disorder. Bartter syndrome shows identical biochemical abnormalities as those found with chronic furosemide therapy. This syndrome is caused by mutations in the furosemide-sensitive Na-K-2Cl cotransporter in the thick ascending loop of Henle. In Gitelman syndrome the characteristic electrolyte and hormonal changes in blood and urine are comparable to those observed in patients treated with thiazide diuretics. This disorder results from mutations in the distal-tubular thiazide-sensitive Na-Cl cotransporter. The two forms of pseudhypoaldosteronism are distinguished by the characteristic metabolic changes encountered with a therapy with potassium-sparing diuretics. The genetic disturbance resides either in the amiloride-sensitive epithelial sodium channel (autosomal-dominant form) or in the spironolactone-sensitive mineralocorticoid receptor (autosomal-recessive form) in the distal tubule and cortical collecting duct. Current research concentrates on defining the structural sites for electrolyte transport and diuretic binding, as well as the molecular mechanisms of transport regulation. This information may allow a more appropriate use of diuretics and the design of new substances with diuretic action.
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PMID:[Pharmacologic action of diuretics in the kidney]. 1089 17

Low-renin hypertension is common and usually implies increased retention of sodium (Na(+)). In every case of known etiology, there is a mineralocorticoid-induced increase in number of epithelial Na(+) channels (ENaCs) in the collecting duct of the kidney, leading to a state of "hyperENaCactivity." In primary aldosteronism, a result of either an adrenal adenoma or bilateral adrenal hyperplasia, aldosterone itself mediates the increase in ENaC function. A severe form of low-renin hypertension in which a molecular mutation in ENaC prevents removal of the channel from the cell surface, known as Liddle's syndrome, results in increased net ENaC activity but, in this case, independently of an increase in aldosterone. Glucocorticoid remedial aldosteronism, an autosomal dominant form of primary aldosteronism, results from a "new" or chimeric gene for aldosterone synthase. Adrenocorticotropic hormone stimulates its expression as well as secretion of aldosterone. Apparent mineralocorticoid excess results from a molecular mutation that allows cortisol to bind to the mineralocorticoid receptor. Both glucocorticoid remedial aldosteronism and apparent mineralocorticoid excess result in an increase in the number of ENaCs. The question remains whether low-renin essential hypertension is related to an increase in ENaC activity. Low-renin hypertension is most common in black patients, who tend to have lower levels of aldosterone as well as renin, which are features that resemble those found in Liddle's syndrome. Preliminary findings suggest that black patients with low-renin hypertension who are resistant to standard antihypertensive therapy respond favorably to the addition of spironolactone, a mineralocorticoid receptor antagonist that reduces ENaC activity.
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PMID:Low-renin hypertension: more common than we think? 1117 96


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