Endothelins as local activators of adrenocortical cells.
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Besides the classical corticotropic hormones, ACTH and angiotensin II, various regulatory peptides produced by the adrenal gland are thought to participate in the control of corticosteroid secretion. Here, we review the evidence that endothelins (ETs) synthesized within the adrenal cortex may act as autocrine and/or paracrine factors to regulate adrenocortical cell activity. The expression of ETs has been detected in normal, hyperplastic and neoplastic adrenocortical cells. The occurrence of ET receptors has been described in the different zones of the cortex. ETs stimulate the secretion of both glucocorticoids and mineralocorticoids, and modulate the proliferation of adrenocortical cells. The effects of ETs on steroidogenic cells are mediated through the activation of various signaling mechanisms including stimulation of phospholipase C, phospholipase A2 and adenylyl cyclase activity, as well as calcium influx through plasma channels. These observations suggest that locally produced ETs may play an important role in the regulation of corticosteroid secretion and in the control of mitogenesis in normal and tumoral adrenocortical cells. (+info)
DAXX, FLASH, and FAF-1 modulate mineralocorticoid and glucocorticoid receptor-mediated transcription in hippocampal cells--toward a basis for the opposite actions elicited by two nuclear receptors?
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Mineralocorticoid (MR) and glucocorticoid (GR) receptors are two closely-related members of the steroid nuclear receptor family of transcription factors that bind common ligands in the brain (corticosterone and cortisol) and supposedly have identical hormone response elements. This raises the important question of how they can elicit differential biological actions in neurons in which they are often colocalized. One plausible explanation is that they differentially recruit proteins (coregulators or other receptor-interacting factors) through cell-specific interactions with regions that diverge between MR and GR to modulate target gene transcription in a receptor-specific manner. We therefore performed a yeast-two-hybrid screening of a human brain cDNA library with an AF1-containing region of the human MR as bait. This screening revealed several potential MR-interacting partners; among them were several clones bearing homology to DAXX, FLASH, and FAF-1, all previously implicated in apoptosis. Coexpression of candidate clones in a mouse hippocampal cell line confirmed these interactions in a mammalian neural cell environment as well. In transient transactivation assays, DAXX and FLASH influenced MR- and GR-driven transcription of the MMTV-Luc reporter similarly; in contrast, although FAF-1 did not transactivate GR, it did selectively stimulate MR-mediated transcription. Thus, the present findings, that 1) DAXX, FLASH, and FAF-1 modulate the transcriptional activities of MR and GR and that 2) FAF-1 selectively coactivates only MR, provide possible clues for how these closely related receptors might differentially influence neuronal function. (+info)
Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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Congenital adrenal hyperplasias (CAH) are inherited defects of cortisol biosynthesis. More than 90% of CAH are caused by 21-hydroxylase deficiency (21-OHD), found in 1:10 000 to 1:15 000 live births. Females with 'classical' 21-OHD, being exposed to excess androgens prenatally, are born with virilized external genitalia. Potentially lethal adrenal insufficiency is characteristic of two-thirds to three-quarters of patients with the classical salt wasting (SW) form of 21-OHD. Non-SW 21-OHD may be diagnosed on genital ambiguity in affected females, and/or later on the occurrence of androgen excess in both sexes. Non-classical 21-OHD, detected in > or =1:100 of certain populations, may present as precocious pubarche in children or polycystic ovarian syndrome in young women. 21-OHD is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombination between CYP21 and the closely linked CYP21P pseudogene. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disorder. This close association between genotype and phenotype makes it possible to predict clinical outcome in affected subjects. The risk of SW and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment, but additional therapies are being developed. A first trimester prenatal diagnosis should be proposed in families in whom molecular studies have been performed previously. The state of heterozygotism can be predicted by hormonal testing and confirmed by molecular studies. Prenatal diagnosis by direct mutation detection in previously genotyped families permits prenatal treatment of affected females in order to avoid or minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before SW crises develop, reducing mortality in this disorder. (+info)
Internal sodium balance in DOCA-salt rats: a body composition study.
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The idea that Na(+) retention inevitably leads to water retention is compelling; however, were Na(+) accumulation in part osmotically inactive, regulatory alternatives would be available. We speculated that in DOCA-salt rats Na(+) accumulation is excessive relative to water. Forty female Sprague-Dawley rats were divided into four subgroups. Groups 1 and 2 (controls) received tap water or 1% saline (salt) for 5 wk. Groups 3 and 4 received subcutaneous DOCA pellets and tap water or salt. Na(+), K(+), and water were measured in skin, bone, muscle, and total body by desiccation and consecutive dry ashing. DOCA-salt led to total body Na(+) excess (0.255 +/- 0.022 vs. 0.170 +/- 0.010 mmol/g dry wt; P < 0.001), whereas water retention was only moderate (0.685 +/- 0.119 vs. 0.648 +/- 0.130 ml/g wet wt; P < 0.001). Muscle Na(+) retention (0.220 +/- 0.029 vs. 0.145 +/- 0.021 mmol/g dry wt; P < 0.01) in DOCA-salt was compensated by muscle K(+) loss, indicating osmotically neutral Na(+)/K(+) exchange. Skin Na(+) retention (0.267 +/- 0.049 vs. 0.152 +/- 0.014 mmol/g dry wt; P < 0.001) in DOCA-salt rats was not balanced by K(+) loss, indicating osmotically inactive skin Na(+) storage. We conclude that DOCA-salt leads to tissue Na(+) excess relative to water. The relative Na(+) excess is achieved by two distinct mechanisms, namely, osmotically inactive Na(+) storage and osmotically neutral Na(+) retention balanced by K(+) loss. This "internal Na(+) escape" allows the maintenance of volume homeostasis despite increased total body Na(+). (+info)
Rapid effects of dexamethasone on intracellular pH and Na+/H+ exchanger activity in human bronchial epithelial cells.
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Glucocorticoids have been shown to produce rapid nongenomic responses in airway epithelia. By using an intracellular pH (pH(i)) spectrofluorescence imaging system and the NH4Cl acid-loading technique, we have shown that the synthetic glucocorticoid,dexamethasone, accelerated intracellular pH recovery after an acid load in a human bronchial epithelial cell line (16HBE14o- cells). Exposure to NH4Cl (20 mm) elicited an intracellular acidification, followed by a pH(i) recovery. Inhibition of the Na+/H+ exchanger decreased the steady-state pH(i) and antagonized the dexamethasone stimulation of pH(i) regulation. The rapid effect of dexamethasone on pH(i) was neither affected by the inhibitor of transcription, cycloheximide, nor by the classical glucocorticoid and mineralocorticoid receptors antagonists, RU486 and spironolactone, respectively. The dexamethasone effect on pH(i) regulation was reduced by inhibitors of adenylate cyclase, cAMP-dependent protein kinase and mitogenactivated protein kinase (ERK1/2). By using a PepTag assay system and Western blotting, we have shown that dexamethasone stimulated cAMP-dependent protein kinase and mitogen-activated protein kinase activities. Taken together our results provide evidence for the rapid stimulation of Na+/H+ exchange activity by glucocorticoids in bronchial epithelial cells via a nongenomic mechanism involving cAMP-dependent protein kinase and mitogen-activated protein kinase ERK1/2 pathways. (+info)
Increased apical targeting of renal ENaC subunits and decreased expression of 11betaHSD2 in HgCl2-induced nephrotic syndrome in rats.
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Nephrotic syndrome is often accompanied by sodium retention and generalized edema. We hypothesize that dysregulation of the epithelial sodium channel (ENaC) and/or of sodium (co)transporters may be responsible for the increased sodium retention associated with HgCl(2)-induced nephropathy. In addition, we examined the hypothesis that the expression of type 2 11beta-hydroxysteroid dehydrogenase (11betaHSD2) is reduced, contributing to the enhanced mineralocorticoid activity. Membranous nephropathy was induced in Brown Norway rats by repeated injections of HgCl(2) (1 mg/kg sc), whereas the control group received only vehicle. After 13 days of treatment, the abundance of ENaC subunits, sodium (co)transporters, and 11betaHSD2 in the kidney was examined by immunoblotting and immunohistochemistry. HgCl(2) treatment induced marked proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and ascites. The protein abundance of alpha-ENaC was increased in the cortex/outer stripe of outer medulla (OSOM) and inner stripe of the outer medulla (ISOM). The protein abundances of beta-ENaC and gamma-ENaC were decreased in the cortex/OSOM while increased in the ISOM. Immunoperoxidase microscopy demonstrated increased targeting of ENaC subunits to the apical plasma membrane in the distal convoluted tubule, connecting tubule, and cortical and medullary collecting duct segments. Moreover, 11betaHSD2 abundance was decreased in cortex/OSOM and ISOM. The protein abundances of type 3 Na/H exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), and thiazide-sensitive Na-Cl cotransporter (NCC) were decreased. Moreover, the abundance of the alpha-1 subunit of the Na-K-ATPase was decreased in the cortex/OSOM and ISOM but remained unchanged in the inner medulla. These results suggest that increased apical targeting of ENaC subunits combined with diminished abundance of 11betaHSD2 may contribute to sodium retention associated with HgCl(2)-induced nephrotic syndrome. The decreased abundance of NHE3, NKCC2, NCC, and Na-K-ATPase may play a compensatory role in promoting sodium excretion. (+info)
Aldosterone: good guy or bad guy in cerebrovascular disease?
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Stroke is a leading cause of disability in the Western world, yet the choices for therapeutic intervention are few. The complex role played by aldosterone in the pathogenesis of stroke is beginning to emerge. Chronic mineralocorticoid receptor (MR) blockade reduces the incidence of hemorrhagic strokes and the severity of damage caused by ischemic strokes. This appears to be a vascular phenomenon because MR blockade increases vessel lumen diameter, which presumably increases blood flow and perfusion of the tissue to reduce ischemic damage. However, the vascular protection afforded by MR antagonism is at odds with the results seen within the brain, where MR activation is required for neuronal survival. Both of these divergent effects have possible therapeutic implications for stroke. (+info)
How does endothelin induce vascular oxidative stress in mineralocorticoid hypertension?
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Endothelin and reactive oxygen species have been identified as important mediators in the pathogenesis of hypertension and associated end-organ damage. In the present issue of Clinical Science, Callera and co-workers have provided new evidence that endothelin stimulates mitochondria to generate reactive oxygen species in the vascular wall during mineralocorticoid-induced hypertension in the rat. These studies open a new line of investigation that could be important for the development of therapeutic strategies; however, there still remains a great deal of uncertainty about the mechanisms that define the relationship between endothelin and oxidative stress in hypertension. (+info)