Role of mineralocorticoid action in the brain in salt‐sensitive hypertension

Oki, Kenji; Gómez-Sánchez, Elise P.; Gómez-Sánchez, Celso E.

doi:10.1111/j.1440-1681.2011.05538.x

Cited by 32 publications

(25 citation statements)

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“…In the meantime, the plasma aldosterone level in both SHRs and WKY rats was lower when compared with their respective controls (Fig 3C). It is well documented that the synthesis of aldosterone increases in response to low plasma sodium so that sodium will be retained in the cell [52]. As such, the increase in sodium as in the present study would certainly secrete low aldosterone.…”

Section: Discussionsupporting

confidence: 49%

Effect of high-salt diet on mean arterial pressure, renal epithelial sodium channels and aquaporin subunits expression levels in Spontaneously Hypertensive Rats

Ramachandran

Gholami

Lam

et al. 2019

Preprint

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27An increase in blood pressure (BP) by a high-salt (HS) diet may involve the 28 changes in the expression of epithelium sodium channels (ENaCs) and aquaporins 29 (AQPs) in the kidney which affect the sodium-and water-handling mechanisms. In the 30 present study, spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats 31 were exposed to HS and regular-salt (RS) diets for 6 weeks and fluid intake was 32 monitored. After 6 weeks, mean arterial pressure (MAP) and plasma hormonal activity 33 of atrial natriuretic peptide (ANP), levels of angiotensin II (Ang II), aldosterone and 34 arginine vasopressin (AVP) were determined. The expression of mRNA and protein 35 levels of ENaC and AQP subunits in kidneys were quantified by real-time PCR and 36 Western blotting. High-salt diet caused higher MAP only in SHRs and higher fluid 37 intake in both strains of rats when compared with their respective controls on RS diet.38 The plasma levels of Ang II and aldosterone were low in both SHRs and WKY rats fed 39 with HS diet. Meanwhile, plasma ANP activity was high in both strains of rats on HS 40 diet; whilst the AVP showed vice versa effects. The renal expression of mRNA and 41 protein levels of α-and γ-ENaCs was lowered by HS diet in both SHRs and WKY rats.42 Although β-ENaC mRNA and protein expression levels were depressed in SHRs but 43 they were enhanced in WKY rats. On the other hand, AQP-1, 2 and 7 mRNA and 44 protein expression levels were lowered in both strains of rats fed with HS diet, while 45 that of AQP-3, 4 and 6 showed no significant changes. The suppression of mRNA and 46 protein expression levels of ENaC and AQP subunits suggests that the HS-induced 47 increase in the MAP of SHRs may not be due to the renal sodium and water retention 48 solely. 49 3 50 Introduction 51 Dietary salt (i.e. sodium chloride, NaCl) intake is the most remarkably modifiable 52 environmental risk factor that attracts many studies on hypertension (HPN). It has been 53 acknowledged as an important contributing factor of the aetiology and progression of 54 HPN [1]. Despite the abundant experimental, interventional and epidemiological 55 observations demonstrating an association between dietary salt and HPN, scepticism 56 remains as to how high salt (HS) intake can be mechanistically linked to the increase in 57 blood pressure (BP). Knowing the heterogeneity of HPN, it is likely to involve the 58 intricate integration of multiple regulatory systems and the kidneys have long been 59 implicated to play a central role in regulating BP. Defects in the kidneys sodium-and 60 water-handling mechanisms have been mooted as one of the primary causes of HPN in 61 HS intake [2]. 62The kidneys have the capacity to return altered BP to baseline level by 63 increasing or decreasing sodium and water excretion in response to elevated or reduced 64 BP [3]. This is accomplished in the kidney by the presence of renal membrane-bound 65 protein i.e. epithelial sodium channel (ENaC) that fine-tune sodium reabsorption [4] 66 and aquaporins (AQPs) that ...

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Section: Discussionsupporting

confidence: 49%

Effect of high-salt diet on mean arterial pressure, renal epithelial sodium channels and aquaporin subunits expression levels in Spontaneously Hypertensive Rats

Ramachandran

Gholami

Lam

et al. 2019

Preprint

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“…The Effect of CS-3150 on Renal Injury in DOCA Rats regulation of blood pressure (Oki et al, 2012;Barrett et al, 2013). For example, Rahmouni et al (2002) reported that intracerebroventricular administration of an MR antagonist decreased SBP in DOCA rats with developed hypertension.…”

Section: Discussionmentioning

confidence: 99%

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Arai

Morikawa

Ubukata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.

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“…Moreover, salt-sensitive hypertension is mitigated by intracerebroventricular administration of MR antagonists (236, 237). Analogous studies suggest similar aldosterone-specific effects on salt appetite (534). It has therefore been postulated that aldosteroneselective central MR modulate blood pressure and salt appetite.…”

Section: Central Regulation Of Blood Pressure and Salt Appetitementioning

confidence: 96%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

735

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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Role of mineralocorticoid action in the brain in salt‐sensitive hypertension

Cited by 32 publications

References 80 publications

Effect of high-salt diet on mean arterial pressure, renal epithelial sodium channels and aquaporin subunits expression levels in Spontaneously Hypertensive Rats

Effect of high-salt diet on mean arterial pressure, renal epithelial sodium channels and aquaporin subunits expression levels in Spontaneously Hypertensive Rats

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

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