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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pregnancy-induced hypertension (PIH) is a frequent cause of maternal and neonatal morbidity and mortality. In the present study we focused on the pathophysiology of PIH, mainly on the role of mineralocorticoids, reversed blood pressure patterns, and the resulting necessity of continuous monitoring of the preeclamptic mother. Problems of antihypertensive therapy are discussed and the first results of a pilot study with Urapidil are presented. To examine the role of mineralocorticoids in the pathophysiology of PIH, we studied plasma aldosterone and 18-hydroxy-corticosterone (18-OH-B) levels in 25 women with PIH and in 25 healthy pregnant women. Furthermore, we evaluated the mineralocorticoid receptor (MR) count in mononuclear leukocytes in the 2 groups. The MR-count was significantly decreased in the PIH-group. The values of plasma aldosterone and 18-OH-B were also low. These results cannot be explained by receptor down-regulation due to higher level of mineralocorticoids of the zona glomerulosa. Perhaps deoxycorticosterone or a hitherto unknown mineralocorticoid is responsible for the hypertension and altered MR-status. The first results of continuous blood pressure measurements with a noninvasive, real-time blood pressure monitor (Finapres) are presented. The comparison of the obtained values with intraarterial measurements demonstrates a good correlation between the two methods. We also report on the first experiences with Urapidil in the treatment of hypertension in severe preeclampsia. The data show that hypertension in preeclamptic women can be treated by Urapidil without side effects or reflex-tachycardia. Further studies will have to prove if Urapidil is suited for prepartal treatment of PIH as well.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Hypertension in pregnancy. 838 33

Effective glucocorticoid inactivation is currently thought to be an indispensable feature of mineralocorticoid target cells. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) inactivates glucocorticoids and prevents them from binding to the non-selective mineralocorticoid receptor. In the kidney it is the NAD dependent high affinity isoform (11 beta-HSD2) which is thought to endow specificity on the receptor. The recent cloning of the human, sheep and rabbit 11 beta-HSD2 enzymes permits a comparison of the enzyme from the three species. Human and rabbit enzymes are 87% identical and of similar length, while the human and sheep enzymes have only 75% identity. The last 12 residues in all three species were found to be highly divergent, but most of the ovine dishomology can be accounted for by the deletion of a single nucleotide toward the C-terminus of the protein resulting in a shift in reading frame generating a protein 27 residues longer than the human isoform. Numerous other deletions were also observed in this region of the sheep cDNA sequence. Furthermore, the rabbit cDNA also displayed a large degree of dishomology with the human sequence a short distance downstream from the termination codon. Conserved overlapping cytoplasmic translocation signals were observed in all three species, suggesting a topology whereby the enzyme is anchored into the endoplasmic reticulum by multiple hydrophobic regions in the N-terminus and the bulk of the 11 beta-HSD2 peptide is sited in the cytoplasm. A polyclonal antibody generated against the C-terminus of human 11 beta-HSD2 was used to localize the enzyme within the kidney. A high level of immunoreactive was observed in distal tubules and collecting ducts, localizing the enzyme to the same part of the nephron as the mineralocorticoid receptor. Moderate levels of staining were also seen in vascular smooth muscle cells. These results support the notion that 11 beta-HSD2 is an autocrine protector of the mineralocorticoid receptor and that it plays an important role in cardiovascular homeostatic mechanisms.
J Steroid Biochem Mol Biol 1995 Dec
PMID:The human 11 beta-hydroxysteroid dehydrogenase type II enzyme: comparisons with other species and localization to the distal nephron. 854 70

To investigate the role of sulfhydryl groups in the interaction of agonists and antagonists with the human mineralocorticoid receptor (hMR) the effect of methyl methanethiosulfonate (MMTS) on free and liganded-hMR was examined. hMR was expressed in insect cells (Sf9) using the baculovirus system. Treatment of cytosol with MMTS at 4 degrees C inhibited the binding to hMR of both [3H]aldosterone and [3H]RU26752 (a synthetic aldosterone antagonist). At 4 degrees C, the sensitivity to MMTS of the liganded-hMR complexes was dependent upon the nature of the ligands: agonists (aldosterone, corticosterone and cortisol) rendered the hMR resistant to MMTS, whereas antagonists (progesterone and RU26752) did not protect the receptor against MMTS inactivation. Analysis of the dose- and time-dependent effects of MMTS revealed that the free hMR and the RU26752-hMR complexes displayed a similar sensitivity to MMTS and that MMTS increased the dissociation of RU26752 from the hMR. At 4 degrees C the aldosterone-hMR complexes were not affected by MMTS treatment, whereas at 20 degrees C MMTS increased the dissociation of aldosterone from hMR. This effect was unrelated to the dissociation of hsp90 from hMR, because the sensitivity of the aldosterone-hmR complexes to MMTS remained unchanged after covalent linkage between hsp90 and the receptor. Our results suggest that agonists and antagonists modify the receptor conformation in distinct ways that render cysteine residues of the ligand binding domain more or less accessible to the MMTS action.
J Steroid Biochem Mol Biol 1996 Mar
PMID:Sulfhydryl groups are involved in the binding of agonists and antagonists to the human mineralocorticoid receptor. 863 67

Domain E, considered as the putative hormone binding domain (HBD) of the human mineralocorticoid receptor (hMR) was expressed in Escherichia coli as a fusion protein with either maltose binding protein (MBP) or glutathione S-transferase (GST). These bacterially-produced MR constructs had no steroid binding activity per se. In fact, heat shock protein association (hsp) is required for high affinity ligand-binding of the MR. After incubation of purified MBP- or GST-HBD with rabbit reticulocyte lysate, known to be rich in heat shock proteins, we obtained saturable binding of [3H]aldosterone. The Kd value for aldosterone was 0.3 nM and the Bmax = 32 pmol/mg. Hormone binding specificity was assessed by competition studies with various steroid ligands. Sucrose gradient assays performed with [3H]aldosterone-MBP-HBD revealed complex sedimenting at 8.3S and 4.9S with [3H]progesterone-MBP-HBD. Western-blot analysis of the sedimentation peak showed the concomitant presence of MBP-HBD by a monoclonal anti-MBP antibody, and hsp90 by a monoclonal anti-hsp antibody. Moreover, following incubation with the anti-rabbit hsp90 monoclonal antibody the sedimenting gradient showed a 10.4S sedimenting complex. These analyses demonstrated that the [3H]aldosterone-MBP-HBD complex is at least associated with hsp90 in reticulocyte lysate and that the HBD of hMR is sufficient to bind hsp90. Deletions of a relatively short amino- (729-766) or carboxy-terminal (940-984) region of the HBD fragment eliminated all steroid-binding properties. Overall, these results indicate that the integrity of domain E is necessary and sufficient to bind steroid ligands, agonists or antagonists, with characteristics similar to the entire native MR.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Putative steroid binding domain of the human mineralocorticoid receptor, expressed in E. coli in the presence of heat shock proteins shows typical native receptor characteristics. 864 16

Vasopressin V1a receptors (V1aRs) are expressed in the septum of the rat brain where they are thought to mediate several of the physiologic and behavioral effects of this neuropeptide. We have investigated the effects of adrenal steroids on forebrain V1aRs. Rats were bilaterally adrenalectomized (ADX) and hormone replaced with either corticosterone (CORT), dexamethasone (DEX) or aldosterone (ALDO) at different concentrations. V1aR mRNA was evaluated using in situ hybridization, and V1aR binding site density was quantified using a specific iodinated V1aR antagonist [125I]d(CH2)5Sar7-AVP (125I-SAVP). V1aR density in the dorsolateral septum and the bed nucleus of the stria terminalis (BNST) decreased significantly with adrenalectomy, and 5 micrograms/100 g b.wt. of DEX was able to restore V1aR binding to levels comparable to those of sham operated controls in both regions. ALDO replacement also elevated V1aR binding in the BNST but not in the septum. In ADX animals given corticosterone in their drinking water, V1aR mRNA levels detected by in situ hybridization increased significantly over the ADX rats given saline. In order to understand the molecular basis of this effect, a putative genomic clone encoding the rat V1aR was isolated, and sequence analysis of the 5' flanking region has revealed the presence of several putative glucocorticoid response elements (GREs). Gel retardation assays were performed using these putative GREs, and two appear to be active in protein binding in glucocorticoid receptor containing nuclear extracts. The glucocorticoid effects on V1aR mRNA and binding, and the presence of putative active GREs in the promoter of the V1aR gene strongly implicate a role for adrenal steroids in the regulation of V1a receptor gene expression in glucocorticoid receptor and/or mineralocorticoid receptor expressing tissues.
Brain Res Mol Brain Res 1996 Jun
PMID:Glucocorticoid regulation of vasopressin V1a receptors in rat forebrain. 879 16

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) converts cortisol into mineralocorticoid receptor inactive cortisone, thus preventing occupation of the non-selective mineralocorticoid receptor by glucocorticoids in the kidney. Mutations generating inactive enzymes have been described in the HSD11B2 gene in the congenital syndrome of apparent mineralocorticoid excess (AME), although proof of mutant protein synthesis was not provided. In the present study we have examined the metabolism of cortisol in mammalian cells transfected with plasmids expressing the wild type and mutant enzymes from three additional families of patients with mutations in the HSD11B2 gene. These studies revealed that the mutants were enzymatically inactive in intact mammalian cells expressing significant levels of both full length and truncated proteins. This is the first study to definitively show that point mutations in the HSD11B2 gene abolish 11 beta HSD2 enzymatic activity in the syndrome of AME.
Mol Cell Endocrinol 1996 May 17
PMID:Point mutations abolish 11 beta-hydroxysteroid dehydrogenase type II activity in three families with the congenital syndrome of apparent mineralocorticoid excess. 879 50

RU486 acts as a potent anti-progestin in humans but does not antagonise progesterone action in the chicken or hamster reflecting a substitution in the ligand binding domain (LBD) of cysteine for glycine in both the chicken and the hamster progesterone receptor (PR), at the position corresponding to codon 722 of the human PR. The tammar wallaby, Macropus eugenii, is also resistant to the effects of RU486. Cloning of a partial cDNA of the PR in the tammar wallaby reveals a glycine to alanine substitution (gly 722 in the human PR), as well as a glutamine to histidine substitution two amino acids upstream of this alanine residue. Both the glycine and glutamine residues are substituted in all three resistant species. These substitutions are also found in the mineralocorticoid receptor, which also does not bind RU486, and suggest an important role for these residues in the formation of the 11-beta pocket of the receptor, which accommodates the bulky side-chains of 11-beta substituted steroids.
Mol Cell Endocrinol 1996 May 31
PMID:The molecular basis of RU486 resistance in the Tammar Wallaby, Macropus eugenii. 880 36

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) protects the non-discriminating mineralocorticoid receptor from occupation by glucocorticoids. In man the enzyme is also highly expressed in the placenta where it is thought to also protect the fetus from the high circulating levels of maternal glucocorticoids. Mutations in the HSD11B2 gene have recently been shown to account for the syndrome of apparent mineralocorticoid excess. In the present study we have used a rat 11 beta HSD2 cDNA to study the distribution and regulation of this enzyme. The rat protein is highly homologous to the mouse, rabbit and human enzymes, except for the carboxy-terminal region which displays extensive divergence between species beyond residue 382. Northern blot analysis of rat total RNA showed that the single copy gene is highly expressed in kidney and adrenal with lower levels in the colon; surprisingly, there was no detectable signal in the placenta. There was also no detectable mRNA in the liver, heart, hippocampus, testis, thymus and pancreas. Nuclease protection analysis revealed the presence of moderate 11 beta HSD2 message levels in the parotid and exceedingly low levels in the placenta. Regulation studies showed that administration of dexamethasone, deoxycorticosterone and 9 alpha-fluorocortisol to adrenalectomized rats for 7 days increased renal enzyme activity 33%-50%, while message levels decreased 35%-70%, suggesting that the increased enzyme activity may represent activation of latent enzyme.
Mol Cell Endocrinol 1996 Jun 18
PMID:Rat 11 beta-hydroxysteroid dehydrogenase type 2 enzyme is expressed at low levels in the placenta and is modulated by adrenal steroids in the kidney. 880 40

Fifty-four steroid homologs, belonging to the series of 17-spirolactones, were modelled by molecular and quantum mechanics. We studied the affinity of these compounds for the cytosolic mineralocorticoid receptor by way of various parameters describing each structure and its molecular properties. After the failure of a classic preliminary QSAR study, demonstrating the nonlinear relationships between affinity and structural descriptors, we constructed a model allowing us to predict the affinity of new compounds. Our method is based on simple graphic tools coupled to a cluster significance analysis. A complementary study of the activity relating the prediction of the antagonist/agonist character of 37 high-affinity compounds was also carried out using the same methodology. The principal electronic and structural characteristics leading to a selective activity were revealed.
J Mol Graph 1995 Dec
PMID:Variable mapping of structure-activity relationships: application to 17-spirolactone derivatives with mineralocorticoid activity. 882 Mar 4

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendelian disorder characterised by end-organ unresponsiveness to mineralocorticoids. Most steroid hormone insensitivity syndromes arise from mutations in the corresponding receptor, but available genetic evidence is against involvement of the mineralocorticoid receptor gene, MLR, in PHA1. A complete genome scan for PHA1 genes was undertaken using homozygosity mapping in 11 consanguineous families. Conclusive evidence of linkage with heterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. The two chromosomal regions harbour genes for subunits of the amiloride-sensitive epithelial sodium channel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle's syndrome are allelic variants caused by mutations in genes encoding subunits of this sodium channel. These genes are of broad biological interest both in relation to sodium and water homeostasis in mammals and by virtue of their homology to the mec genes of Caenorhabditis elegans involved in mechanosensitivity and neuronal degeneration.
Hum Mol Genet 1996 Feb
PMID:Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping. 882 86


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