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Abstract

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

The mineralocorticoid receptor (MR) has been called a promiscuous receptor because its intrinsic affinity for aldosterone, cortisol and corticosterone is similar. Since glucocorticoids circulate in concentrations 100- to 1000-fold those of aldosterone, stoichiometry dictates that MR should be activated by glucocorticoids, not aldosterone, yet MRs are expressed in many tissues and regulate diverse functions, many of them under the regulation of the renin–angiotensin–aldosterone system. A relatively small number of brain MRs are aldosterone selective and modulate blood pressure. Evidence for possible mechanisms conferring ligand specificity in the context of mineralocorticoid-induced hypertension and the brain are discussed. These include factors (or mechanisms) intrinsic to the receptor, such as alternative splice variants and translation start sites, and extrinsic to the MR, including differential access through the blood–brain barrier, differential recruitment of co-regulators and scaffolding proteins, 11β-steroid dehydrogenase activity, synthesis of potent acylated aldosterone derivatives and the synthesis of relevant amounts of aldosterone in areas of the brain that modulate blood pressure.


Historical perspective

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

Soon after its isolation, it was recognized that the potent mineralocorticoid deoxycorticosterone acetate (DOCA) could alleviate Addisonian crises, but in excess produced hypertension and damaged the heart and kidneys, particularly if paired with a high salt intake (Selye & Hall, 1943; Knowlton et al. 1949). Despite early evidence that other organs were also directly involved in the hypertension of mineralocorticoid excess (Langford & Snavely, 1959), for many years the predominant thought was that the action aldosterone was limited to water and electrolyte transport in the kidney.

Mineralocorticoid actions in the brain

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

Autoradiographic studies in the late 1970s demonstrated overlapping but distinct binding of aldosterone and corticosterone in the rat brain (Stumpf & Sar, 1979; Birmingham et al. 1984). Both steroids were most heavily retained in the hippocampus, followed by circumventricular organs and select nuclei of the brainstem, while aldosterone binding in the cortex, thalamus and brainstem was more widespread and greater than that of corticosterone. The importance of specific nuclei of the anterior hypothalamus, circumventricular organs, particularly the floor of the third ventricle and area postrema, and central sympathetic nervous system in renovascular and mineralocorticoid–salt-induced hypertension was established several years later by work in DOCA-resistant rats (Lassman & Mulrow, 1974) and a large series of ablation studies (reviewed by Brody et al. 1991). Proof that the mineralocorticoid receptor (MR) in the brain mediated these effects came from diverse studies (reviewed by Gomez-Sanchez, 2004). The chronic intracerebroventricular (i.c.v.) infusion of aldosterone at rates that do not alter the blood pressure when infused systemically increases the blood pressure of rats and dogs. In addition, i.c.v. infusions of inhibitors of the MR and the epithelial sodium channel, an effector of aldosterone action, prevent the onset and mitigate established systemic mineralocorticoid–salt-induced hypertension (reviewed by Gomez-Sanchez, 2004). These studies have been confirmed in other laboratories (Huang et al. 2006).

Distribution and effects of the MR

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

Mineralocorticoid receptors are expressed most abundantly in hippocampal neurons, less in sodium-transporting epithelia of the nephron, colon and choroid plexus, and even less in many other organs, including blood vessels, heart and nuclei of the anterior hypothalamus, amygdala and brainstem that participate in haemodynamic homeostasis and salt appetite (Gomez-Sanchez, 2004; Gomez-Sanchez et al. 2006). While excessive mineralocorticoid activation of MRs in hypothalamic and circumventricular nuclei increases blood pressure by increasing central sympathetic drive to the kidney, heart and vascular smooth muscle and release of arginine vasopressin, and decreasing baroreceptor sensitivity (reviewed by Janiak et al. 1990; Gomez-Sanchez, 2004), its effects in the hippocampus are quite different. While corticosterone replacement mitigates the effects of adrenalectomy on the hippocampal serotonergic system and on affect and learning, aldosterone replacement does not (De Kloet et al. 1983).

Ligand specificity of the MR

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

Unlike receptors of the epithelial cells of the kidney tubules and colon responsible for ion and fluid transport that bind aldosterone with high affinity and specificity, the hippocampus has high-affinity ‘corticosteroid-preferring sites’ that bind aldosterone, corticosterone and cortisol with similar affinity, but are primarily occupied by physiological concentrations of corticosterone and cortisol (reviewed by De Kloet, 1991). Other ‘dexamethasone-preferring sites’ bind endogenous glucocorticoids with lower affinity and aldosterone with even less affinity (Funder et al. 1973; Krozowski & Funder, 1983; De Kloet et al. 2000). Once the MR gene was cloned, it could be confirmed that the affinity of the isolated recombinant MR for aldosterone, cortisol and corticosterone was similar (Arriza et al. 1987). Potential intrinsic mechanisms for ligand specificity, including splice variants and alternative translation initiation sites, were found and studied, but to date none explains ligand specificity in different tissues in vivo (Zhou et al. 2000; Pascual-Le Tallec & Lombes, 2005; Viengchareun et al. 2007). Verification that the MR was a ‘promiscuous receptor’ (Funder, 1995) led to a conundrum; given that concentrations of glucocorticoids in the blood are 100- to 1000-fold greater than those of aldosterone, how can aldosterone, even at concentrations attained in primary aldosteronism, compete with glucocorticoids to bind and activate the MR in mineralocorticoid target tissues?

11β-Hydroxysteroid dehydrogenase enzymes

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

Glucocorticoids are metabolized by the 11β-hydroxysteroid dehydrogenase types 1 and 2 (11β-HSD1 and HSD2). 11β–Hydroxysteroid dehydrogenase type 1 is expressed in many tissues, including the brain, but especially the liver. It can act as a dehydrogenase that converts cortisol and corticosterone to inactive forms in vitro, depending on substrate and cofactor availability, but is a reductase in most tissues, converting inactive 11–dehydro metabolites into active glucocorticoids, thus amplifying the impact of circulating levels of glucocorticoids upon the glucocorticoid receptor (GR) and MR (Gomez-Sanchez et al. 1997b; Seckl & Walker, 2001). The other 11β-hydroxysteroid dehydrogenase, 11β-HSD2, was first demonstrated in the kidney. 11β–Hydroxysteroid dehydrogenase type 2 only has dehydrogenase activity and inactivates cortisol and corticosterone by converting them to their 11–dehydro forms. In the 1980s it was demonstrated that the co-expression of 11β-HSD2 with MRs in transport epithelial cells conferred extrinsic aldosterone selectivity to these MRs by lowering intracellular glucocorticoid levels (Edwards et al. 1988; reviewed by Gomez-Sanchez et al. 2003). Since 11β-HSD2 expression is very low in the adult brain, it has been difficult to measure, and it appeared that most MRs in the CNS were normally occupied by glucocorticoids (Moisan et al. 1990; Gomez-Sanchez & Gomez-Sanchez, 1992; Seckl et al. 1993). Recently, with use of more sophisticated techniques and antibodies, the co-expression of MRs and 11β-HSD2 has been demonstrated in a small number of unique, previously uncharacterized neurons of the nucleus tractus solitarii that appear to have an important influence on neurons mediating sodium appetite and blood pressure (Geerling et al. 2005, 2006a,b; Geerling & Loewy, 2006a,b).

Activity of 11β-HSD1

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

Since 11β-HSD1 has bidirectional activity, it was not clear in early studies that there were two different enzymes. The obligate cofactor for 11β-HSD1 reductase activity is reduced nicotinamide adenine dinucleotide phosphate (NADPH). Without hexose-6-phosphate dehydrogenase (H6PDH), to generate NADPH, 11β-HSD1 is a dehydrogenase (Atanasov et al. 2004). We investigated the possibility that expression of 11β-HSD1 without H6PDH would confer aldosterone specificity to MRs in presumed aldosterone target areas of the brain, for example in the choroid plexus, where MRs, the epithelial sodium channel and 11β-HSD1, but not 11β-HSD2, are highly expressed (Gomez-Sanchez et al. 1996, 2008). However the distributions of 11β-HSD1 and H6PDH message and protein were similar, and we found no evidence that 11β-HSD1 might be predominantly a dehydrogenase in the brain (Gomez-Sanchez et al. 2008). Notwithstanding, the efficiency with which tritiated corticosterone is converted to 11–dehydrocorticosterone by minces of brain tissue belies the limited amount of 11β-HSD2 protein detected in the brain. Other evidence suggests the existence of another dehydrogenase enzyme, however none has been confirmed to date (Gomez-Sanchez et al. 1996; Gomez-Sanchez & Gomez-Sanchez, 2001).

Intracellular factors that confer MR ligand affinity

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

In addition to factors that alter local concentrations of ligand, there are intracellular factors that confer MR ligand affinity. The MR is a ligand-dependent nuclear receptor that is a transcription factor for multiple genes (genomic effects). It also initiates rapid non-genomic effects mediated by classical cell signalling pathways (reviewed by Grossmann et al. 2005; Connell & Davies, 2005). Other potential extrinsic determinants of MR ligand specificity, of as yet unknown but probably considerable importance, are the differential expression of chaperone and scaffolding proteins, transcription co-regulators and other proteins that associate with the MR and are essential to or modulate specific functions (Fuller & Young, 2005; Pascual-Le Tallec & Lombes, 2005; Viengchareun et al. 2007).

Steroids are lipophilic and cross cell membranes freely. Though access of aldosterone, corticosterone and cortisol to the brain is limited somewhat by multiple drug resistance 1-type P–glycoproteins (Uhr et al. 2002), their concentrations in the brain reflect those in the blood (Gomez-Sanchez et al. 2005a), so differential access to certain areas of the brain or specific cells is unlikely to be the only factor providing extrinsic ligand selectivity.

Potentiation of endogenous aldosterone activity

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

We confirmed and extended studies describing an aldosterone derivative formed in the heart that was significantly more potent than aldosterone (Lockett, 1969). We have demonstrated that several acylated aldosterone derivatives that are potentially formed in vivo are significantly more potent than aldosterone in producing hypertension when infused i.c.v. Unfortunately, these derivatives are rapidly converted to aldosterone by esterases in blood, and we have yet to isolate and identify such a derivative in vivo (Gomez-Sanchez et al. 2001).

Extra-adrenal synthesis of aldosterone

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

The extra-adrenal synthesis of aldosterone in or near aldosterone target cells of the brain is a potential mechanism to circumvent high systemic levels of glucocorticoids and provide independence from regulation by the peripheral renin–angiotensin–aldosterone system. All enzymes necessary for the synthesis of aldosterone from cholesterol have been demonstrated in the brain of rats (Mellon, 1994; Gomez-Sanchez et al. 1996, 1997a) and humans (Yu et al. 2002). Brain minces from adrenalectomized rats synthesized aldosterone from endogenous substrate and converted 3H-deoxycorticosterone to 3H-aldosterone in vitro (Gomez-Sanchez et al. 1996, 1997a), and aldosterone is synthesized in the normal rat brain in vivo (Gomez-Sanchez et al. 2005a). However, the amount of aldosterone produced in the brain is too small relative to adrenal production to study its regulation in the adrenal-intact animal; hence, the relevance of aldosterone synthesis in the brains of normal animals is not known. We turned to a genetically hypertensive rat that resembles a rat with chronic systemic mineralocorticoid excess in several important ways.

The Dahl salt-sensitive (SS) rat

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

The Dahl salt-sensitive (SS) rat is a model of human salt-sensitive hypertension studied since the late 1960s. Manoeuvres involving the CNS that prevent or mitigate mineralocorticoid–salt-induced hypertension in normal rats also prevent salt-induced hypertension in SS rats, including ablation of the anteroventral third ventricle area (Goto et al. 1981) and central sympathetic nervous system (Takeshita et al. 1979; Mark, 1991) and the i.c.v. infusion of MRs and epithelial sodium channel antagonists (reviewed by Gomez-Sanchez, 2004). However, plasma aldosterone concentrations in the SS rat are normal (Rapp & Dene, 1985) and are suppressed as expected by a high-salt diet (Pacha & Pohlova, 1993). To determine whether differences in the expression of MR or 11β-HSD isoforms might cause increased MR-mediated effects in the brains of SS rats, we used primers and methods described by us (Gomez-Sanchez et al. 2003, 2006, 2008) to measure their mRNA. We found no difference in the message for the MR and 11β-HSD1 and 11β-HSD2, or H6PDH levels in brains and adrenals between SS rats and Sprague–Dawley rats. Since the hypertension of SS rats has a central MR component, though their plasma aldosterone was normal, we tested the possibility that extra-adrenal aldosterone synthase (AS) in the brain was responsible for at least part of their hypertension. Inhibitors of steroidogenesis were infused i.c.v. at doses too low to inhibit adrenal steroidogenesis when they entered the systemic circulation. 19–Ethynyl-deoxycorticosterone, an inhibitor of aldosterone synthase and 11β-hydroxylase (Gomez-Sanchez et al. 1996), trilostane, an antagonist of the 3β-hydroxysteroid dehydrogenase (Gomez-Sanchez et al. 2005b), and FAD286, a specific aldosterone synthase inhibitor (E.P. Gomez-Sanchez, C.M. Gomez-Sanchez, M. Plonczynski and C.E. Gomez-Sanchez, unpublished observations), prevented the increase in blood pressure of SS rats upon dietary salt challenge, suggesting that excessive aldosterone synthesis in the brain of SS rats is involved in their hypertension.

Overexpression of aldosterone synthase in neurons

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix

The aetiology of the hypertension and end-organ disease in the Dahl SS rat involves many genes and mechanisms. We created a transgenic rat that overexpresses AS in neurons, the Syn1/AS transgenic rat, as a tool to study the effect of increased aldosterone production in the brain in isolation from the many systemic changes produced by mineralocorticoid excess, as well as the complex genetic aetiologies of the hypertension of the Dahl SS rat (E.P. Gomez-Sanchez & C.E. Gomez-Sanchez, unpublished observations). Since AS is the last enzyme in a complex cascade of reactions, we predicted that the increase in aldosterone production would be restricted to neurons that normally express the requisite upstream enzymes and cofactors for the conversion of cholesterol to deoxycorticosterone, the substrate for AS. We also predicted that total aldosterone production would not differ, because the amount produced by the brain would be relatively low compared with that of the adrenal and that regulation by the renin–angiotensin–aldosterone system would modulate adrenal production to keep circulating aldosterone levels within the physiological range. The mRNA for AS is about 100-fold greater in the brains of the Syn1/AS transgenic rats compared with the wild-type, yet aldosterone plasma levels and 24 h production are the same. The Syn1/AS transgenic rat raised on a standard maintenance rat chow (Teklad, Indianapolis, IN, USA; 0.4% NaCl) is moderately but significantly hypertensive compared with age-matched Sprague–Dawley rats by 10 weeks of age (145 ± 5 versus 123 ± 6 mmHg systolic blood pressure), and preliminary data indicate that it is predisposed to heart failure with age. Whether the end-organ damage is due to the stress of high blood pressure alone or to other factors, including an increase in circulating inflammatory cytokines, as presented by Felder (2009) in this issue of Experimental Physiology, is not yet known.

References

  1. Top of page
  2. Abstract
  3. Historical perspective
  4. Mineralocorticoid actions in the brain
  5. Distribution and effects of the MR
  6. Ligand specificity of the MR
  7. 11β-Hydroxysteroid dehydrogenase enzymes
  8. Activity of 11β-HSD1
  9. Intracellular factors that confer MR ligand affinity
  10. Potentiation of endogenous aldosterone activity
  11. Extra-adrenal synthesis of aldosterone
  12. The Dahl salt-sensitive (SS) rat
  13. Overexpression of aldosterone synthase in neurons
  14. Conclusion
  15. References
  16. Appendix
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