Mineralocorticoid Receptors In Kidney Research Articles

Apparent mineralocorticoid excess in Israel: a case series and literature review.

Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2, leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature. Retrospective cohort study. Clinical, laboratory, and molecular data from patients' records were collected. Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation. In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.

Uncovering a Mineralocorticoid Receptor-Dependent Adipose-Vascular Axis: Implications for Vascular Dysfunction in Obesity?

Obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are associated with increased levels of aldosterone and activation of cardiovascular mineralocorticoid receptors (MRs) contributing to hypertension and associated cardiovascular disease (CVD) (1). Large randomized controlled trials such as the Randomized Aldactone Evaluation Study (RALES), the Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) have demonstrated the CVD-related mortality and morbidity benefits of MR antagonists, further implicating MR signaling as a key mediator of CVD (2). The actions of kidney MR signaling to increase cardiovascular and renal fibrosis and blood pressure is well known; however, recent research suggests that inappropriate activation of extrarenal MR signaling in vascular endothelial cells (ECs), vascular smooth muscle cells (VSMCs), immune cells, and adipocytes promotes insulin resistance, T2DM, and associated CVD (1,3,4). For example, in association with obesity and insulin resistance, perivascular and visceral adipose tissue (PVAT and VAT) is dysfunctional, in part, because of adipose MR activation (3). Furthermore, PVAT and VAT secrete aldosterone, the ligand for MRs in endothelial and smooth muscle cells, and this is increased in obesity (3, …

Lipocalin‐2 Deficiency Protects against Aldosterone‐Induced Hypertension and Organ Damages by Inhibiting Mineralocorticoid Receptor Signaling

Lipocalin‐2, an adipokine dysregulated in cardiometabolic syndrome, is causatively involved in the development of obesity‐related endothelial dysfunction and hypertension. The present study investigated the contribution of lipocalin‐2 to aldosterone‐induced pathologies involving mineralocorticoid receptors (MR). Mice were treated during four weeks with vehicle, angiotensin II or challenged with the combination of aldosterone plus uninephrectomy and administration of 1% saline in the drinking water (ANS). In mice without lipocalin‐2 (LKO), the gene expression levels of MR in heart, kidney, adipose tissue and aorta are significantly lower than those of wild‐type (WT) controls. ANS significantly increased arterial blood pressures in WT but not LKO mice. Moreover, lipocalin‐2 deficiency prevented ANS‐induced fibrotic damages in heart and kidneys. Treatment with the MR antagonist, spironolactone, protected mice against ANS‐induced hypertension and organ damages to a similar extent as lipocalin‐2‐deficiency. On the other hand, angiotensin II‐induced elevation of blood pressure was not affected significantly by either lipocalin‐2‐deficiency or MR inhibition. The mechanistic involvement of lipocalin‐2 in aldosterone‐stimulated MR expression and/or activation was further investigated. Collectively, the results demonstrate that lipocalin‐2 plays a critical role in the cardiovascular damage induced by activation of the aldosterone‐MR signaling axis.Support or Funding InformationThis work was supported by the grants from Hong Kong Research Grant Council [General Research (17121714, HKU 763312 and HKU 780613M), Collaborative Research Fund (C7055‐14G)] and an educational grant from Les Laboratories Servier (RS100503).

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology.

The mineralocorticoid receptor (MR) and its ligand aldosterone are the principal modulators of hormone-regulated renal sodium reabsorption. In addition to the kidney, there are several other cells and organs expressing MR, in which its activation mediates pathologic changes, indicating potential therapeutic applications of pharmacological MR antagonism. Steroidal MR antagonists have been used for decades to fight hypertension and more recently heart failure. New therapeutic indications are now arising, and nonsteroidal MR antagonists are currently under development. This review is focused on nonclassic MR targets in cardiac, vascular, renal, metabolic, ocular, and cutaneous diseases. The MR, associated with other risk factors, is involved in organ fibrosis, inflammation, oxidative stress, and aging; for example, in the kidney and heart MR mediates hormonal tissue-specific ion channel regulation. Genetic and epigenetic modifications of MR expression/activity that have been documented in hypertension may also present significant risk factors in other diseases and be susceptible to MR antagonism. Excess mineralocorticoid signaling, mediated by aldosterone or glucocorticoids binding, now appears deleterious in the progression of pathologies that may lead to end-stage organ failure and could therefore benefit from the repositioning of pharmacological MR antagonists.

Synthesis of 6,19-cyclopregnanes. Constrained analogues of steroid hormones

A procedure for the synthesis of 6,19-cyclopregnanes is described involving an intramolecular alkylation reaction of Delta(4)-3-keto steroids with a 19-mesylate in the presence of KOH in isopropanol. Three 6,19-cyclopregnanes were prepared (4, 5 ,9); in the rat, 6,19-cycloprogesterone (4) and its 21-hydroxy derivative 5 displaced [3H]-dexamethasone from glucocorticoid receptors, the former compound being more active. Both compounds did not compete with [3H]-aldosterone for kidney mineralocorticoid receptors nor with [3H]-R5020 for uterus progesterone receptors.

Aldosterone makes human endothelium stiff and vulnerable

Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies identified these classic receptors also in the vascular system. Indeed, aldosterone alters structure and function of human endothelium. We applied nanotechniques to detect these changes. Experiments were performed in cultured monolayers of human umbilical vein endothelial cells (HUVECs). Ten nanomoles per liter aldosterone or solvent (control) was added to the culture medium for 72 hours. Atomic force microscopy (AFM) was used as a nanotool that physically interacts with the cell surface. In the monolayer we measured cell volume, apical cell surface, and cell stiffness. Volume, apical surface area, and stiffness of individual cells increased in response to aldosterone by 18% (P < 0.05), 64% (P < 0.001), and 78% (P < 0.01), respectively. Imaging of the cell-to-cell contacts disclosed gaps in response to aldosterone. Furthermore, underneath the monolayer we detected an aldosterone-induced increase of protein deposition by 58% (P < 0.001). Aldosterone remodels human endothelium in vitro. Cells increase in size and stiffness. Protein leakage through intercellular gaps could be caused by the increased apical membrane tension. The increase in cell rigidity could trigger endothelial dysfunction observed in hyperaldosteronism.

Human endothelium: target for aldosterone.

Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies demonstrated the presence of these receptors in nonclassical locations, including the cardiovascular system. We tested the hypothesis whether endothelial cells respond to aldosterone with changes in cell volume, a measure for ion-mediated water movement across the cell membrane. By means of atomic force microscopy in fluid, we measured volume of adherent human umbilical venous endothelial cells exposed for 72 hours to 10 nmol/L aldosterone. Over this period of time, cells swell by approximately 18%. Aldosterone-induced swelling is prevented by 100 nmol/L of the mineralocorticoid receptor antagonist spironolactone, added to the primary endothelial cell culture. Aldosterone-treated cells dramatically shrink when 1 micromol/L of the diuretic amiloride is applied. Cells deprived of aldosterone do not respond to amiloride. Our conclusions are: (1) aldosterone leads to sustained cell swelling inhibited by administration of spironolactone or the sodium channel blocker amiloride; (2) cells respond to amiloride after aldosterone exposure; (3) renal diuretics act on endothelial cells; and (4) both amiloride and spironolactone could be useful for medical applications to prevent aldosterone-mediated endothelial dysfunction.

Oxidative stress induced by L-buthionine-( S, R)-sulfoximine, a selective inhibitor of glutathione metabolism, abrogates mouse kidney mineralocorticoid receptor function

In vitro studies have demonstrated that cysteine groups present in most of the steroid receptors play an essential role in the steroid binding process as well as in the ability of this superfamily of signaling proteins to function as transcription factors. However, there is poor experimental evidence, if any, which demonstrates that under conditions of oxidative stress the steroid receptors in general, and the mineralocorticoid receptor in particular, are affected in vivo in a similar fashion as has been described for cell-free systems or cells in culture. In the present work we report that when mice are exposed to oxidative stress by treatment with L-buthionine-( S, R)-sulfoximine ( L-( S, R)-BSO), a glutathione depleting agent, the aldosterone-dependent mineralocorticoid biological response (measured as sodium retention and potassium elimination) was diminished in a directly proportional manner with respect to the depletion of renal glutathione. Accordingly, the steroid binding capacity of the mineralocorticoid receptor was also abrogated, whereas the receptor protein level remained unchanged. The harmful effects observed in mice after glutathione depletion were efficiently prevented by co-treatment with glutathione monoethyl ester. Similar inhibition in the steroid binding capacity was also generated in vitro by receptor alkylation and receptor oxidation, an effect which was prevented in the presence of reducing agents. Since the glutathione deficit generated in vivo by treatment with L-( S, R)-BSO did not significantly affect other renal proteins which are known to be required for the mineralocorticoid mechanism of action, we suggest that in renal cells a low redox potential exerts drastic and uncompensated inhibition of the receptor-mediated mineralocorticoid biological response. This effect was ascribed to the loss of steroid binding capacity of oxidized receptor, most likely by modification of essential cysteines as supported by experiments where a decreased number of reactive thiols and reduced covalent binding of thiol-reactive ligand were evidenced on immunopurified receptor after in vivo treatment with L-( S, R)-BSO .

Comparative inhibition by hard and soft metal ions of steroid-binding capacity of renal mineralocorticoid receptor cross-linked to the 90-kDa heat-shock protein heterocomplex

We analysed the inhibitory effects in vitro and in vivo of several metal ions on aldosterone binding to the rat kidney mineralocorticoid receptor with the purpose of assessing possible toxic effects of those ions on sodium retention, as well as to obtain information on receptor structural requirements for ligand binding. For the assays in vitro, the inhibitory effects of 20 metal ions were analysed on steroid-binding capacity for renal receptor cross-linked to 90-kDa heat-shock protein (hsp90) by pretreatment with dimethyl pimelimidate. Cross-linking prevented the artifactual dissociation of hsp90 (and, consequently, the loss of steroid binding) from the mineralocorticoid receptor due to the presence of high concentrations of salt in the incubation medium. Cross-linked heterocomplex showed no difference in ligand specificity and affinity with respect to native receptor, but increased stability upon thermal- or ionic-strength-induced destabilization was observed. Treatments in vitro with metal ions in the range 10(-8)-10(-1) M resulted in a differential inhibitory effect for each particular ion on aldosterone binding. Using the negative logarithm of metal concentration for 50% inhibition, the ions could be correlated with their Klopman hardness constants. The analysis of this relationship led us to postulate three types of reaction: with thiol, imidazole and carboxyl groups. The essential role played by these residues in steroid binding was confirmed by chemical modification of cysteines with dithionitrobenzoic acid, histidines with diethyl pyrocarbonate and acidic amino acids with Woodward's reagent (N-ethyl-5-phenylisoxazolium-3'-sulphonate). Importantly, the toxic effects of some metal ions were also observed by treatments in vivo of adrenalectomized rats on both steroid-binding capacity and aldosterone-dependent sodium-retaining properties. We suggest that those amino acid residues are involved in the activation process of the mineralocorticoid receptor upon steroid binding. Thus toxic effects observed with these metal ions may be a consequence of modifications of those essential groups. Our results support the notion that toxicity of metals on renal mineralocorticoid function may be predicted according to their chemical hardness.

Tautomycin inhibits phosphatase-dependent transformation of the rat kidney mineralocorticoid receptor

The binding of aldosterone (ALDO) to the mineralocorticoid receptor (MR) induces a conformational change of the protein referred to as ‘transformation’. This feature can be evidenced in vivo by the capacity of the MR to interact with chromatin, and in vitro by the ability of the MR to bind to DNA strands or to shift the sedimentation coefficient ( S) to lower values. The transformation process allows MR to work as a transcription factor after interacting with specific sequences of DNA. The signal transduction pathway for the MR transformation remains unknown. As a first step towards elucidating the mechanism of steroid-dependent MR transformation, we asked if the MR-signaling pathway is affected by the phosphorylation status of the MR-heterocomplex, and how that pathway may be regulated. Incubation of preformed [ 3H]ALDO-MR complex with bovine intestinal alkaline phosphatase led to an increase in the rate of MR-transformation (measured as 9.4–5.4 S shift). This alkaline phosphatase-dependent MR transformation was inhibited by the specific alkaline phosphatase-type inhibitor levamisole, and was not evident in incubations performed with acid phosphatases. A direct correlation between the DNA-cellulose binding capacity of the [ 3H]ALDO-MR complex and the percentage of transformed 5.4 S MR form was also observed. When rat kidney cytosol was incubated in the absence of both exogenous phosphatase and stabilizing agents (such as molybdate or vanadate), MR transformation also took place, in a time- and temperature-dependent process. In contrast with the inhibitory effect observed upon alkaline phosphatase-promoted transformation, levamisole was unable to inhibit the endogenous transforming activity of MR, suggesting that an endogenous phosphatase other than those which belong to the alkaline-type may be responsible for that transformation. Tautomycin, a polyketide produced by the soil bacteria Streptomyces which inhibits serine/threonine phosphatases of the PP1/PP2A subgroup, was able to inhibit the endogenous phosphatase activity in a concentration-dependent form ( K i app =7.35 nM). These results support the idea that the endogenous renal activity involved in the regulation of rat kidney MR transformation may be a protein phosphatase which belongs to the PP1/PP2A subgroup.

Native rat kidney mineralocorticoid receptor is a phosphoprotein whose transformation to a DNA-binding form is induced by phosphatases.

Addition of alkaline phosphatase to rat kidney cytosol diminishes the ability of the mineralocorticoid receptor (MR) to bind aldosterone in a time-, temperature- and concentration-dependent form. A variety of phosphatase inhibitors, including levamisole, are effective in preventing this inactivation. On the other hand, when the steroid-receptor complex is incubated in the presence of alkaline phosphatase, an increment in the rate of receptor transformation is evidenced by a change in the sedimentation coefficient from 8.8 S to 5.1 S, as well as increased DNA-binding capacity. The effects of alkaline phosphatase on activation and transformation can also be observed when the MR is incubated at 20 degreesC in the cytosolic medium, indicating that the catalytic action of an endogenous phosphatase may be involved in the transformation process. The ability of phosphatase inhibitors such as levamisole for suppressing both alkaline phosphatase- and endogenous phosphatase-directed transformation does not correspond well between them. Evidence is presented to affirm that the endogenous phosphatase activity is not due to an alkaline phosphatase-type, but it may be due to a protein serine/threonine phosphatase, as evidenced by the inhibitory effects of okadaic acid. The experimental results also show direct evidence that the MR undergoes phosphorylation in a physiological milieu.

21-Hydroxy-6,19-oxidoprogesterone: a novel synthetic steroid with specific antiglucocorticoid properties in the rat.

In the rat, the conformationally highly bent steroid 21-hydroxy-6, 19-oxidoprogesterone efficiently displaces [3H]corticosterone from thymus-glucocorticoid receptors and blocks type II receptors in kidney cytosols but competes with neither [3H]aldosterone for kidney-mineralocorticoid receptors nor [3H]progesterone for uterus-progesterone receptors. It evokes Na+ retention only at very high doses (approximately 100 microg/100 g of rat weight) and is unable to induce tyrosine aminotransferase or to increase glycogen deposits in rat liver. When coincubated with corticosterone or dexamethasone, 2.5 microM 21OH-6OP inhibits 80% of tyrosine aminotransferase induction. It may therefore be used experimentally as an antiglucocorticoid virtually lacking mineralocorticoid or glucocorticoid properties as well as affinity for mineralocorticoid or progesterone receptors.

Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies.

Adrenalectomized weanling rats injected with [3H]aldosterone plus excess RU486, with or without a range of doses of nonradioactive aldosterone or corticosterone, show tissue-specific patterns of competition for tracer binding to mineralocorticoid receptors (MR). From detailed dose-response curves, corticosterone in vivo shows approximately 3% the apparent affinity of aldosterone for MR in colon and kidney, approximately 30% for those in the heart, and approximately 300% in the hippocampus. We interpret these data as evidence that 1) relatively low levels of aldosterone cross the blood-brain barrier; and 2) specificity-conferring mechanisms in addition to the exclusion of corticosterone from epithelial MR are required for selective aldosterone action in sodium homeostasis.

Glucocorticoid receptor, mineralocorticoid receptors, 11β-hydroxysteroid dehydrogenase-1 and -2 expression in rat brain and kidney: in situ studies

In mammals, 11β-hydroxysteroid dehydrogenase (11-HSD) activity allows aldosterone occupancy of mineralocorticoid receptors (MR) by inactivating endogenous glucocorticoids. The present study examined the distribution of 11-HSD2, 11-HSD1, glucocorticoid receptor (GR) and MR in kidney and brain. High levels of expression of 11-HSD2 were found in renal cortical distal tubules and more diffusely expressed in distal tubules of the medulla. No expression of 11-HSD2 was found on serial sectioning of the brain. 11-HSD1 was expressed in proximal tubules of the kidney and throughout the brain. GR mRNA was found predominantly in renal proximal tubules and diffusely in brain, while MR mRNA was located in the renal distal tubules and also in various brain nuclei. These anatomical findings support a functional relationship between 11-HSD1 and GR in both brain and kidney, but between 11-HSD2 and MR in kidney only.

The role of development and adrenal steroids in the regulation of the mineralocorticoid receptor messenger RNA.

The ontogeny, adrenal-feedback regulation and regional distribution of the mineralocorticoid receptor (MR) mRNA were examined in the rat brain and kidney. In the kidney, MR mRNA levels in the adult were only 25-30% of the neonatal concentration. Adrenalectomy caused a 35% increase in total brain MR mRNA and a 94% increase in kidney MR mRNA levels. Examination of the regional distribution of the MR mRNA within the brain revealed that the hippocampus had the highest levels, and the mRNA abundance increased after adrenalectomy. The administration of dexamethasone to intact animals resulted in a significant reduction of MR mRNA in the kidney of neonatal rats but not in the brain. These data indicate that there are developmental changes in MR gene expression in kidney and that adrenal steroids can modulate MR gene expression in both the brain and kidney.

Differential regulation of mouse mammary tumor virus-bacterial chloramphenicol acetyltranferase chimeric gene by human mineralocorticoid hormone-receptor complexes

The brain tissues of the rat and mouse express two types of corticosteroid binding proteins, the glucocorticoid (GR) and aldosterone (MR) receptors. Unlike the type II (GR) receptor, type I receptor has a high affinity for aldosterone (ALDO) and corticosterone and is structurally similar to the kidney mineralocorticoid receptor (MR). The results reported in this study provide direct evidence for the interation of dexamethasone (DEX), triamcinolone acetonide (TA), dexamethasone-21-mesylate (DXM) and 11-deoxycorticosterone (DOC) with human MR expressed in cells by transient co-transfection of a hMR expression vector. The interactions of hMR with DEX, TA, DXM, DOC, promegestone (R5020) and methyltrienelone (R1881) were measured by trans-activation of mouse mammary tumor virus long terminal repeat fused to bacterial chloramphenicol acetytransferase (MMTV-tk-CAT) in gene co-transfection experiments and by cell free hormone binding assay. The incubation of various steroid hormones in the presence of [ 3H]ALDO in a competition assay with extracts prepared from HeLa cells co-transfected with hMR expression vector, showed that hMR expressed under these conditions has a high relative affinity for DEX which is similar to ALDO, TA and DOC. Incubation with DXM under these conditions showed very little competition, as was observed with R1881 and R5020. Incubation of the co-transfected cells with DEX, ALDO, DOC, R5020, TA, R1881 and DXM demonstrated that the level of trans-activation did not reflect the previously observed order of binding affinity for the hMR. The level of trans-activation was always higher with DEX and TA compared to ALDO and DOC. Analysis of the binding of labeled glucocorticoid regulatory element (GRE) and hMR incubated with DEX, ALDO and DXM by gel shift analysis demonstrated that the trans-activation of MMTV-tk-CAT by hMR is a result of the interaction of hMR with GRE in the MTTV-LTR.

Molecular Cloning of a Mineralocorticoid (Type I) Receptor Complementary DNA from Rat Hippocampus

Rat brain expresses two types of corticosteroid-binding proteins. The type I receptor binds corticosterone with high affinity and is structurally related to the kidney mineralocorticoid receptor (MR), while the type II or classical glucocorticoid receptor binds corticosterone with lower affinity and displays an in vivo preference for dexamethasone. Here we describe the isolation and characterization of a cDNA coding for the MR, from a rat hippocampus cDNA library, by low stringency hybridization to radiolabeled human glucocorticoid receptor cDNA. The nucleotide and deduced amino acid sequence for rat hippocampal MR displays extensive homology to a MR cDNA isolated from human kidney, suggesting that they are orthologous genes. Southern analysis suggests that there is only one gene for the MR, and in vitro expression of the receptor generates a high affinity corticosterone-binding protein. These data provide evidence to support the contention that a single gene gives rise to the MR in renal tissues and type I receptors in the brain.

How can aldosterone act as a mineralocorticoid?

The circulating levels of glucocorticoid hormones are commonly several orders of magnitude higher than those of the mineralocorticoid aldosterone. Paradoxically, cytosol Type I receptors from a variety of tissues, or recombinant-derived human kidney mineralocorticoid receptors, have essentially indistinguishable affinity for aldosterone, corticosterone and cortisol. In vivo, however, though injected corticosterone and aldosterone are equivalently taken up and retained by rat hippocampus or heart, binding of corticosterone is very much lower in classical mineralocorticoid target tissues (kidney, parotid, colon). The genesis of this aldosterone-selectivity in vivo appears to be the expression, in physiologic mineralocorticoid target tissues, of the microsomal enzyme 11β hydroxysteroid dehydrogenase (11βOHSD). Whereas cortisol and corticosterone have affinity for Type I receptors equivalent to

Feedback action and tonic influence of corticosteroids on brain function: A concept arising from the heterogeneity of brain receptor systems

Two types of corticosteroid receptors can be distinguished in rat brain. The type 1 receptor resembles the kidney mineralocorticoid receptor and has two functional expressions in brain, i.e. type 1 corticosterone (CORT) preferring sites (CR) and mineralocorticoid receptors (MR). The type 2 receptor is similar to the liver glucocorticoid receptor (GR). CORT binds to both CR and GR. The localization, binding specificity, and capacity of the receptor systems have served as criteria to evaluate steroid dependent events in brain biochemistry and behaviour. The GR is widely distributed in neurons and glial cells, with the highest density in frontal brain regions. The GR becomes occupied concomitant with rising plasma CORT levels after stress and as part of the circadian rhythm. The GR mediates the feedback action of CORT on stress-activated brain processes. The CR has its predominant localization in neurons of the septo-hippocampal complex and has a ten-fold higher affinity for CORT than that of the GR. The CR is, at all times of intact adrenocortical secretion, 90% or more occupied by endogenous hormone. The CR mediates a tonic influence exerted with stringent specificity by CORT on hippocampus-associated functions, e.g. cognition, mood, and affect. CORT, via the CR, thus contributes to hippocampus function in interpretation of sensory information, leading to appropriate neuroendocrine and behavioural responses, which are themselves subsequently subject to feedback action via the GR. The MR mediates the mineralocorticoid effect on salt and water balance and its behavioural corollary of salt appetite. The anatomical localization of the MR system is as yet ill-defined, although functional studies suggest circumventricular organs as mineralocorticoid target sites. The CR and the MR have in common the high affinity for mineralocorticoids, but the CR is defined by its exclusive responsiveness to CORT as its agonist. The CR and MR probably represent the same chemical receptor modality (type 1), which is expressed differentially depending on the presence of extravascular corticosteroid binding globulin (CBG) in the vicinity of the receptor. GR capacity is subject to autoregulation. Chronic stress, senescence, and chronic CORT administration reduce GR number, with, as a consequence, a less efficient feedback signal. The CR number seems not to be under the control of corticosteroids, probably since the receptor sites are extensively occupied by endogenous hormones. The CR number displays a circadian rhythm and is reduced during senescence. The reduced number of CR sites, but not of GR sites, is restored to the same number as in the hippocampus of young control animals after chronic treatment with the behaviourally active ACTH(4–9) analogue, ORG 2766. CR capacity thus seems to be regulated by neural factors.

Function and plasticity of brain corticosteroid receptor systems: Action of neuropeptides

Two types of corticosteroid receptors may be distinguished in rat brain. Type 1 resembles the kidney mineralocorticoid receptor and Type 2 is similar to the liver glucocorticoid receptor (GR). Type 1 receptor system displays two functional expressions, i.e. Type 1 corticosterone (CORT)-preferring sites (CR) and Type 1 mineralocorticoid receptors (MR). MR occurs in circumventricular organs and mediates behaviors such as salt appetite. CR has its principal localization in neurons of the hippocampus, and mediates tonic influences of CORT on hippocampus-associated functions. CR responds with stringent specificity to CORT. Differentiation between CR and MR is due to a different accessibility of the receptor by CORT and ALDO, which seems dependent on the presence of extravascular corticosteroid binding globulin (CBG). GR has a wide distribution in brain, occurs in neurons and glial cells and has its principal localization in such regions as the paraventricular nucleus and the n. tractus solitarii (site of CRF synthesis and of blood pressure regulation, respectively). GR mediates the feedback action of CORT on stress-activated brain processes. GR is subject to autoregulation by CORT. Chronic stress, senescence, and chronic CORT administration reduce receptor number, while GR capacity is increased after adrenalectomy. Reduced GR receptor number results in a less-efficient feedback action. The CORT signal via CR probably can only be altered via changes in CR density evoked rather by neural factors than by autoregulation. CR density is reduced at senescence, but is increased to receptor number of young control animals after chronic treatment with a behaviorally potent ACTH-(4–9) analogue, Org 2766. CR plasticity is prominent for the hippocampus, which is a structure involved in cognition, emotional state and subtle regulation of pituitary-adrenal function.