Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have produced and characterized lines of transgenic mice expressing a fusion gene composed of the pituitary expression-specific promoter region of the POMC gene, driving the herpes simplex viral-1 thymidine kinase. Adult mice were treated with the antiherpes agent ganciclovir at 70 mg/kg body weight (ip, twice daily for 10-12 days). Approximately 98% of the pituitary intermediate lobe melanotropes and anterior lobe corticotropes were ablated as determined by immunocytochemistry and RIA specific for the POMC-derived peptides, ACTH, beta-endorophin, and alpha-MSH. The number of lactotropes, somatotropes, thyrotropes, and gonadotropes was not altered compared with controls, indicating that in the adult pituitary, POMC products are not required to maintain the distribution of cell types. As expected, plasma corticosterone levels were substantially decreased after POMC cell ablation. In situ hybridization studies showed that the mouse ACTH receptor was expressed uniformly throughout the adrenal cortex, and RNase protection assays revealed that the ACTH receptor mRNA decreased after pituitary POMC cell ablation. Additionally, RNase protection assays showed that pituitary POMC cell ablation resulted in the decrease of adrenal p450c11 beta transcripts while p450c11AS (aldosterone synthase) mRNA levels remained constant. These data demonstrate differential regulation of steroid pathway-specific enzymes by POMC products. Our results also suggest that the thymidine kinase cell obliteration technique may not be dependent on cell division as a prerequisite for cytotoxicity, thus supporting the idea that targeted molecular ablation using cell- and tissue-specific promoter sequences to drive viral thymidine kinase expression can be refined further to study other nonmitotic cells.
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PMID:Targeted ablation of pituitary pre-proopiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland. 747 75

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary cause of human hypertension in which aldosterone secretion is regulated by adrenocorticotropin (ACTH). A genetic mutation which causes GRA has recently been identified in our laboratory, a hybrid or chimeric gene fusing nucleotide sequences of the 11 beta-hydroxylase and aldosterone synthase genes. The finding that these chimeric gene duplications are sensitive and specific markers for GRA allows for a simple, direct genetic test for this disorder. In preliminary studies, we found a wide range of blood pressure levels (including normotension) in affected GRA subjects. Studies to data indicate that this is not related to environmental factors such as sodium intake. Another possibility is that chimeric gene expression is variable, with low blood pressure subjects having reduced gene expression. However, the data have not demonstrated differences in steroid levels in subjects with severe versus mild hypertension. In fact, it is likely that the wide range in blood pressure levels in affected subjects involves interaction of other systems which control blood pressure. Preliminary data in two kindreds suggest that blood pressure levels are reciprocally related to levels of urinary kallikrein excretion, supporting the notion that GRA is a hypertension-predisposing syndrome, with the resultant blood pressure the interaction of the gene mutation with other blood pressure regulatory systems. Although GRA is a mineralocorticoid excess state, as evidenced by profoundly suppressed levels of plasma renin activity, we have observed (contrary to the reported literature) that normokalemia is a typical finding. In one large normokalemic pedigree, preliminary findings indicate that these subjects have a normal capacity to excrete potassium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucocorticoid-remediable aldosteronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis. 779 15

1. In familial hyperaldosteronism type I (FH-I), expression of an adrenocorticotropic hormone (ACTH)-dependent hybrid 11 beta-hydroxylase/aldosterone synthase gene causes excessive 'hybrid steroid' (18-hydroxy- and 18-oxo-cortisol) production. In order to study the mechanism of elevated 'hybrid steroid' levels in angiotensin-unresponsive (AII-U) aldosterone-producing adenoma (APA), we compared responses of 24 h urinary 18-oxo-cortisol, aldosterone and cortisol to dexamethasone (0.5 mg q6h for 4 days) in 11 FH-I patients, 11 patients with AII-U APA, 11 patients with AII-responsive (AII-R) APA and 10 patients with bilateral adrenal hyperplasia (BAH). 2. Consistent, marked suppression (by at least 60%) of 18-oxo-cortisol levels by dexamethasone was seen in all groups except AII-U APA. Aldosterone levels were consistently suppressed to undetectable levels only in FH-I. Cortisol levels were suppressed to undetectable levels in all patients except two with AII-U APA. 3. Production of both 18-oxo-cortisol and aldosterone (and occasionally cortisol) in AII-U APA appears relatively ACTH-independent, consistent with a common mechanism involved in the formation of these two steroids from their respective precursors, which differs from that in FH-I. 4. In AII-R APA and BAH, 18-oxo-cortisol production appears markedly ACTH-dependent, but aldosterone production is not.
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PMID:Production of 18-oxo-cortisol in subtypes of primary aldosteronism. 880 May 94

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11 beta-hydroxylase or 17 alpha-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the HSD11K (HSD11B2) gene.
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PMID:Inherited forms of mineralocorticoid hypertension. 895 79

Increasing evidence suggests that mineralo- and glucocorticoids modulate cardiovascular homeostasis via the effects of circulating components generated within the adrenals but also through local synthesis. The aim of this study was to assess the existence of such a steroidogenic system in heart. Using the quantitative reverse transcriptase-polymerase chain reaction, the terminal enzymes of corticosterone and aldosterone synthesis (11beta-hydroxylase and aldosterone synthase, respectively) were detected in the rat heart. This pathway was shown to be physiologically active, since production of aldosterone, corticosterone, and their precursor, deoxycorticosterone, was detected in both the homogenate and perfusate of isolated rat hearts using radioimmunoassay after Celite column chromatography. Perfusion of angiotensin II or adrenocorticotropin for 3 h increased aldosterone and corticosterone production and decreased deoxycorticosterone, suggesting that aldosterone and corticosterone are formed within the isolated heart from a locally present substrate. Chronic regulation of this intracardiac system was then examined. As in adrenals cardiac 11beta-hydroxylase and aldosterone-synthase mRNAs were independently regulated by 1 week's treatment with either low sodium and high potassium diet (which increased aldosterone synthase mRNA level only), angiotensin II (which raised level of both mRNAs), or adrenocorticotropin (which stimulated the 11beta-hydroxylase gene exclusively). Changes in cardiac steroid levels during treatment were not directly related to their plasma levels suggesting independent regulating mechanisms. This study, therefore, provides the first evidence for the existence of an endocrine cardiac steroidogenic system in rat heart and emphasizes its potential physiological and pathological relevance.
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PMID:Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. 947 30

The effects and action mechanisms of estradiol on aldosterone secretion in female rats were studied. Replacement of estradiol benzoate (EB) increased the levels of plasma estradiol and aldosterone in ovariectomized (Ovx) rats. The aldosterone release from zona glomerulosa (ZG) cells was higher in EB-treated rats than in oil-treated animals. EB treatment potentiated the responses of aldosterone release to adrenocorticotropic hormone (ACTH), forskolin (FSK), and 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP). Administration of EB in vivo did not alter cAMP production in response to ACTH or FSK. Although angiotensin II (Ang II) increased aldosterone secretion by rat ZG cells, the stimulatory effect of Ang II on the release of aldosterone was not altered by EB treatment. The conversions of [3H]-deoxycorticosterone to [3H]-corticosterone and [3H]-corticosterone to [3H]-aldosterone in EB-treated groups were greater than those in the oil-treated group. These results suggest that estradiol increases aldosterone secretion in part through the mechanisms involving the activation of the post-cAMP pathway, 11beta-hydroxylase and aldosterone synthase activity.
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PMID:Effects of estradiol on aldosterone secretion in ovariectomized rats. 1008 32

Aldosterone and cortisol are the major mineralocorticoid and glucocorticoid produced by the human adrenal. Circulating levels of angiotensin II and potassium control the adrenal production of aldosterone, while the production of cortisol is controlled mainly by adrenocorticotropin. The capacity of the adrenal cortex to differentially produce aldosterone and cortisol relies to a large degree on the expression of aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1). CYP11B2 catalyzes the final steps in the biosynthesis of aldosterone and is expressed solely in the glomerulosa of the adrenal cortex, while CYP11B1 catalyzes the final steps in the biosynthesis of cortisol and is expressed in the fasciculata/reticularis. The zonal expression of these two isozymes appears to result from transcriptional regulation of the two genes. Herein, the recent progress in defining the cellular mechanisms that regulate transcription of these two isozymes and thus the capacity of the adrenal gland to differentially produce aldosterone and cortisol is discussed.
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PMID:Adrenal zonation: clues from 11beta-hydroxylase and aldosterone synthase. 1041 30

In vivo and in vitro experiments were designed to assess the effect of testosterone on aldosterone secretion in male rats. Orchidectomized rats were injected subcutaneously with oil or testosterone propionate ([TP] 2 mg/kg) for 7 days. Intact rats were injected with oil only. The results indicate that the plasma aldosterone level was higher in orchidectomized versus intact and TP-replaced rats. In the in vitro study, testosterone caused a marked decrease of aldosterone secretion by zona glomerulosa (ZG) cells, but failed to alter the accumulation of intracellular adenosine 3',5'-cyclic monophosphate (cAMP). Testosterone significantly decreased the corticotropin (ACTH)-stimulated production of aldosterone and accumulation of cAMP in rat ZG cells. The conversion of corticosterone to aldosterone and of 25-OH-cholesterol to pregnenolone, as well as angiotensin II (ANG II)-stimulated production of aldosterone, were decreased by testosterone. These results suggest that testosterone inhibits the basal and ANG II- and ACTH-stimulated release of aldosterone, via inhibition of aldosterone synthase activity and cytochrome P-450 side-chain cleavage (P450scc) activity, and ACTH-stimulated cAMP accumulation in rat ZG cells.
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PMID:Inhibition of aldosterone production by testosterone in male rats. 1048 49

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

Oral hormone substitution for the treatment of Addison's disease inadequately replaces the physiologic circadian secretion of corticosteroids. Alternative therapeutic approaches are reimplantation of healthy autologous adrenal tissue and allogeneic transplantation (Tx), respectively. The aim of our study was to evaluate the functional capacity of adrenal grafts and the influence of intercellular adhesion molecule-1 (ICAM-1) on graft survival. Fragmented adrenal glands of wild-type B10.BR (H-2k) and wild-type or ICAM-1-deficient BALB/c (H-2d) mice were transplanted underneath the kidney capsule of adrenalectomized B10.BR mice [complete major histocompatibility complex (MHC) haplotype disparity in the latter]. Postoperatively, the endocrine function of the adrenal grafts was evaluated by the following parameters: (1) survival analysis of the recipients (termination at day 70 after Tx); (2) reverse transcription-polymerase chain reaction expression analysis of aldosterone synthase (zona glomerulosa-specific) and of 11b-hydroxylase (zona fasciculata-specific); and (3) measurement of basal adrenocorticotropic hormone (ACTH) stimulated serum corticosterone levels. Expression of both enzyme-specific mRNAs was detected in the grafts at any time during the post-Tx period. The adrenal grafts of syngeneic and surviving MHC-disparate mice displayed a similar basal hormone secretion, which was about 60% lower than that in sham-operated animals. In the transplanted mice, ACTH-stimulated corticosterone measurement revealed a 5- to 10-fold decreased functional reserve capacity. ICAM-1 deficiency significantly prolonged the survival of adrenal grafts. Fragmented adrenal grafts are able to maintain physiologic basal corticosterone levels but had markedly reduced reserve capacity. Nevertheless, the results give rise to hopes that autologous or MHC-compatible allogeneic transplantation of adrenal grafts may replace oral hormone substitution in humans.
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PMID:Transplantation of adrenal tissue fragments in a murine model: functional capacities of syngeneic and allogeneic grafts. 1201 74


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