Faculty Opinions recommendation of Conditional deletion of hsd11b2 in the brain causes salt appetite and hypertension.

Hypoxic-ischemic injury (HI) to the neonatal human brain results in myelin loss that, in some children, can manifest as cerebral palsy. Previously, we had found that neuronal overexpression of the bone morphogenic protein (BMP) inhibitor noggin during development increased oligodendroglia and improved motor function in an experimental model of HI utilizing unilateral common carotid artery ligation followed by hypoxia. As BMPs are known to negatively regulate oligodendroglial fate specification of neural stem cells and alter differentiation of committed oligodendroglia, BMP signaling is likely an important mechanism leading to myelin loss. Here, we showed that BMP signaling is upregulated within oligodendroglia of the neonatal brain. We tested the hypothesis that inhibition of BMP signaling specifically within neural progenitor cells (NPCs) is sufficient to protect oligodendroglia. We conditionally deleted the BMP receptor 2 subtype (BMPR2) in NG2-expressing cells after HI. We found that BMPR2 deletion globally protects the brain as assessed by MRI and protects motor function as assessed by digital gait analysis, and that conditional deletion of BMPR2 maintains oligodendrocyte marker expression by immunofluorescence and Western blot and prevents loss of oligodendroglia. Finally, BMPR2 deletion after HI results in an increase in noncompacted myelin. Thus, our data indicate that inhibition of BMP signaling specifically in NPCs may be a tractable strategy to protect the newborn brain from HI.

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Mineralocorticoid Receptors and Glucocorticoid Receptors in HPA Stress Responses During Coping and Adaptation

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.266 ◽

2020 ◽

Cited By ~ 4

Author(s):

Edo Ronald de Kloet ◽

Marian Joëls

Keyword(s):

Stress Response ◽

Stress Responses ◽

Coping Style ◽

Glucocorticoid Receptors ◽

Memory Storage ◽

Salt Appetite ◽

Mineralocorticoid Receptors ◽

Stress Response System ◽

Appraisal Processes ◽

The Brain

The glucocorticoid hormones cortisol and corticosterone coordinate circadian events and are master regulators of the stress response. These actions of the glucocorticoids are mediated by mineralocorticoid receptors (NR3C2, or MRs) and glucocorticoid receptors (NR3C1, or GRs). MRs bind the natural glucocorticoids cortisol and corticosterone with a 10-fold higher affinity than GRs. The glucocorticoids are inactivated only in the nucleus tractus solitarii (NTS), rendering the NTS-localized MRs aldosterone-selective and involved in regulation of salt appetite. Everywhere else in the brain MRs are glucocorticoid-preferring. MR and GR are transcription factors involved in gene regulation but recently were also found to mediate rapid non-genomic actions. Genomic MRs, with a predominant localization in limbic circuits, are important for the threshold and sensitivity of the stress response system. Non-genomic MRs promote appraisal processes, memory retrieval, and selection of coping style. Activation of GRs makes energy substrates available and dampens initial defense reactions. In the brain, GR activation enhances appetitive- and fear-motivated behavior and promotes memory storage of the selected coping style in preparation of the future. Thus, MRs and GRs complement each other in glucocorticoid control of the initiation and termination of the stress response, suggesting that the balance in MR- and GR-mediated actions is crucial for homeostasis and health.

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Hepatic contribution to satiation of salt appetite in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1986.251.6.r1095 ◽

1986 ◽

Vol 251 (6) ◽

pp. R1095-R1102 ◽

Cited By ~ 6

Author(s):

M. G. Tordoff ◽

J. Schulkin ◽

M. I. Friedman

Keyword(s):

Portal Vein ◽

Sodium Concentration ◽

Reciprocal Relationship ◽

Dietary Sodium ◽

Salt Appetite ◽

Nacl Solution ◽

Hepatic Portal Vein ◽

Hepatic Portal ◽

Portal Vein Infusion ◽

The Brain

We examined the influence of hepatic-portal vein infusion of NaCl and of hepatic vagotomy on 3% NaCl solution drinking by sodium-deficient rats. Combined dietary sodium restriction and administration of the natriuretic agent, furosemide (5 mg), produced a vigorous appetite for 3% NaCl solution that was attenuated by portal infusion of NaCl. Whereas infusions (1 ml/30 min) of NaCl into the hepatic-portal vein in concentrations as low as 0.15 M (isotonic) significantly reduced 3% NaCl consumption, a higher concentration (0.6 M) infused into the jugular vein, or portal infusions of KCl (0.6 M) or sucrose (1.2 M), were ineffective. Rats with selective hepatic vagotomy displayed an attenuated appetite for salt whether or not they received hepatic-portal NaCl. This was not due to altered excretion of sodium. Taken together, these results suggest that the liver or portal vein can provide a sodium-specific neural signal capable of attenuating the appetite for salt and this information is transferred to the brain by fibers in the hepatic vagus that fire in reciprocal relationship with portal sodium concentration.

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7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome

Journal of Applied Physiology ◽

10.1152/japplphysiol.01361.2011 ◽

2012 ◽

Vol 112 (5) ◽

pp. 704-710 ◽

Cited By ~ 63

Author(s):

Rebecca A. Johnson ◽

Maxine Lam ◽

Antonio M. Punzo ◽

Hongda Li ◽

Benjamin R. Lin ◽

...

Keyword(s):

Disease Progression ◽

Rett Syndrome ◽

Developmental Disorder ◽

Body Weight Loss ◽

Autism Spectrum ◽

Mutant Mice ◽

Disease Symptoms ◽

Neuronal Nuclei ◽

Conditional Deletion ◽

The Brain

Rett syndrome (RTT), caused by mutations in the methyl-CpG binding protein 2 gene ( MECP2), is a debilitating autism spectrum developmental disorder predominantly affecting females. Mecp2 mutant mice have reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; conditional deletion and overexpression of BDNF in the brain accelerates and slows, respectively, disease progression in Mecp2 mutant mice. Thus we tested the hypothesis that 7,8-dihydroxyflavone (7,8-DHF), a small molecule reported to activate the high affinity BDNF receptor (TrkB) in the CNS, would attenuate disease progression in Mecp2 mutant mice. Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.

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Recent Advances in the Endogenous Brain Renin-Angiotensin System and Drugs Acting on It

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1155/2021/9293553 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Aswar Urmila ◽

Patil Rashmi ◽

Ghag Nilam ◽

Bodhankar Subhash

Keyword(s):

Endocrine System ◽

Renin Angiotensin System ◽

Pain Modulation ◽

Salt Appetite ◽

Angiotensin System ◽

Renin Angiotensin ◽

Recent Advances ◽

The Central Nervous System ◽

Pleiotropic Properties ◽

The Brain

The RAS (renin-angiotensin system) is the part of the endocrine system that plays a prime role in the control of essential hypertension. Since the discovery of brain RAS in the seventies, continuous efforts have been put by the scientific committee to explore it more. The brain has shown the presence of various components of brain RAS such as angiotensinogen (AGT), converting enzymes, angiotensin (Ang), and specific receptors (ATR). AGT acts as the precursor molecule for Ang peptides—I, II, III, and IV—while the enzymes such as prorenin, ACE, and aminopeptidases A and N synthesize it. AT1, AT2, AT4, and mitochondrial assembly receptor (MasR) are found to be plentiful in the brain. The brain RAS system exhibits pleiotropic properties such as neuroprotection and cognition along with regulation of blood pressure, CVS homeostasis, thirst and salt appetite, stress, depression, alcohol addiction, and pain modulation. The molecules acting through RAS predominantly ARBs and ACEI are found to be effective in various ongoing and completed clinical trials related to cognition, memory, Alzheimer’s disease (AD), and pain. The review summarizes the recent advances in the brain RAS system highlighting its significance in pathophysiology and treatment of the central nervous system-related disorders.

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Role of renin-angiotensin-aldosterone system in NaCl appetite of rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1985.248.1.r1 ◽

1985 ◽

Vol 248 (1) ◽

pp. R1-R11 ◽

Cited By ~ 9

Author(s):

M. J. Fregly ◽

N. E. Rowland

Keyword(s):

Angiotensin Ii ◽

Control Level ◽

Sodium Concentration ◽

Salt Appetite ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Consequent Reduction ◽

The Brain ◽

Additional Point

A variety of experimental paradigms is now known to induce an appetite for NaCl solutions in rats. These include 1) bilateral adrenalectomy; 2) hypothyroidism; 3) salivariectomy; and 4) administration of hydrochlorothiazide, metyrapone, estrogen, methylxanthines, captopril, propranolol, large doses of deoxycorticosterone acetate, and intraperitoneal isotonic glucose or subcutaneous polyethylene glycol. A point of commonality among these is that a reduction in preference threshold accompanies the appetite for NaCl in all cases thus far tested. An additional point is the fact that each paradigm inducing a salt appetite, except salivariectomy, can be linked to an effect on the renin-angiotensin-aldosterone system. The level of angiotensin II in the brain may play a role in the induction of a salt appetite in the rat. It is clear, however, that modest doses of mineralocorticoid hormones, given in conjunction with the stimulus producing the salt appetite (e.g., adrenalectomy, thyroidectomy, or treatment with captopril), reduces NaCl intake to control level. Although this effect can be partially explained in most cases by the consequent reduction in angiotensin II production, the salt appetite that occurs when mineralocorticoid concentration in blood is high and angiotensin II concentration is low, or when both are low, requires another explanation. This may be related to the effect of mineralocorticoid hormones on salivary sodium concentration. The role of the concentration of sodium in saliva on intake of NaCl solution provides an alternative explanation for the induction of a salt appetite in rats and merits additional study.

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Glucocorticoids increase salt appetite by promoting water and sodium excretion

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00294.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R1444-R1451 ◽

Cited By ~ 32

Author(s):

Robert L. Thunhorst ◽

Terry G. Beltz ◽

Alan Kim Johnson

Keyword(s):

Urinary Excretion ◽

Sodium Excretion ◽

Saline Solution ◽

Salt Appetite ◽

Total Fluid Intake ◽

Glucocorticoid Treatment ◽

Water Excretion ◽

Sodium Ingestion ◽

Water And Sodium Excretion ◽

The Brain

Glucocorticoids [e.g., corticosterone and dexamethasone (Dex)], when administered systemically, greatly increase water drinking elicited by angiotensin and sodium ingestion in response to mineralocorticoids [e.g., aldosterone and deoxycorticosterone acetate (DOCA)], possibly by acting in the brain. In addition, glucocorticoids exert powerful renal actions that could influence water and sodium ingestion by promoting their excretion. To test this, we determined water and sodium intakes, excretions, and balances during injections of Dex and DOCA and their coadministration (DOCA+Dex) at doses commonly employed to stimulate ingestion of water and sodium. In animals having only water to drink, Dex treatment greatly increased water and sodium excretion without affecting water intake, thereby producing negative water and sodium balances. Similar results were observed when Dex was administered together with DOCA. In animals having water and saline solution (0.3 M NaCl) to drink, Dex treatment increased water and sodium excretion, had minimal effects on water and sodium intakes, and was associated with negative water and sodium balances. DOCA treatment progressively increased sodium ingestion, and both water and sodium intakes exceeded their urinary excretion, resulting in positive water and sodium balances. The combination of DOCA+Dex stimulated rapid, large increases in sodium ingestion and positive sodium balances. However, water excretion outpaced total fluid intake, resulting in large, negative water balances. Plasma volume increased during DOCA treatment and did not change during treatment with Dex or DOCA+Dex. We conclude that increased urinary excretion, especially of water, during glucocorticoid treatment may explain the increased ingestion of water and sodium that occurs during coadministration with mineralocorticoids.

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Glucocorticoid and mineralocorticoid regulation of angiotensin II type 1 receptor binding and inositol triphosphate formation in WB cells

Journal of Endocrinology ◽

10.1677/joe.0.1620381 ◽

1999 ◽

Vol 162 (3) ◽

pp. 381-391 ◽

Cited By ~ 25

Author(s):

SG Shelat ◽

LM Flanagan-Cato ◽

SJ Fluharty

Keyword(s):

Angiotensin Ii ◽

Cell Line ◽

At1 Receptor ◽

Inositol Triphosphate ◽

Epithelial Cell Line ◽

Salt Appetite ◽

Pressor Responses ◽

The Brain

Mineralocorticoids, glucocorticoids, and angiotensin II (AngII) act cooperatively to maintain body fluid homeostasis. Mineralocorticoids, such as aldosterone and deoxycorticosterone-acetate (DOCA), function synergistically with AngII in the brain to increase salt appetite and blood pressure. In addition, glucocorticoids increase AngII-induced drinking and pressor responses and may also facilitate the actions of aldosterone on salt appetite. The AngII Type 1 (AT1) receptor mediates many of the physiological and behavioral actions of AngII. This receptor is coupled to the G-protein Gq, which mediates AngII-induced inositol triphosphate (IP3) formation. The WB cell line, a liver epithelial cell line that expresses the AT1 receptor, was used to examine the cellular basis of glucocorticoid and mineralocorticoid regulation of AT1 function. In this study corticosterone and dexamethasone treatments increased the number of AT1 receptors by activating the glucocorticoid receptor (GR). This increase in AT1 binding resulted in enhanced AngII-stimulated IP3 formation. However, only supraphysiological doses of aldosterone or DOCA increased AT1 binding, and this effect also was mediated by GR activation. Furthermore, despite evidence that mineralocorticoids and glucocorticoids function together to increase AngII-stimulated actions in vivo, aldosterone and dexamethasone did not act synergistically to affect AT1 binding, Gq expression, or IP3 formation. These results indicate that GR activation, and the subsequent increases in AT1 binding and in AngII-stimulated IP3 formation, may represent a cellular mechanism underlying the synergy between adrenal steroids and AngII.

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Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite

Physiological Genomics ◽

10.1152/physiolgenomics.00007.2002 ◽

2002 ◽

Vol 9 (2) ◽

pp. 113-120 ◽

Cited By ~ 34

Author(s):

Satoshi Morimoto ◽

Martin D. Cassell ◽

Curt D. Sigmund

Keyword(s):

Functional Role ◽

Salt Intake ◽

Pressor Response ◽

Renin Angiotensin System ◽

Electrolyte Balance ◽

Salt Appetite ◽

Specific Expression ◽

The Brain

The brain renin-angiotensin system (RAS) has an important role in the regulation of cardiovascular function. In the brain, angiotensinogen (AGT) is expressed mainly in astrocytes (glia) and in some neurons in regions controlling cardiovascular activities. Because of the inability to dissect the functional role of astrocyte- vs. neuron-derived AGT in vivo by pharmacological approaches, the exact role of neuron-derived AGT in the regulation of blood pressure (BP) and fluid and electrolyte balance remains unclear. Therefore, we generated a transgenic mouse model overexpressing human AGT under the control of a neuron-specific (synapsin I) promoter (SYN-hAGT). These mice exhibited high-level expression of human AGT mRNA in the brain, with lower expression in the kidney and heart. Human AGT was not detected in plasma, but in the brain it was expressed exclusively in neurons. Intracerebroventricular (30 ng) but not intravenous (500 ng) injection of purified human renin (hREN) caused a pressor response, which was prevented by intracerebroventricular preinjection of the angiotensin II type 1 receptor antagonist losartan, indicating an AT1 receptor-dependent functional role of neuron-derived AGT in the regulation of BP in response to exogenous REN. Double transgenic mice expressing both the hREN gene and SYN-hAGT transgene exhibited normal BP and water intake but had an increased preference for salt. These data suggest that neuronal AGT may play an important role in regulating salt intake and salt appetite.

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