Mineralocorticoid receptors in vascular function and disease

McCurley, Amy; Jaffe, Iris Z.

doi:10.1016/j.mce.2011.06.014

Cited by 153 publications

(172 citation statements)

References 125 publications

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“…Excessive aldosterone/MR signaling may be deleterious for vessels, as impaired vascular reactivity observed in subjects with aldosterone-producing adrenal adenoma, hypertension, or heart failure can be improved by the use of MR antagonists (4,20,21). It has been suggested that the vascular pathological effects of aldosterone/MR result from inflammation, increased vascular reactive oxygen species, and decreased nitric oxide production (4,22,23).…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that the vascular pathological effects of aldosterone/MR result from inflammation, increased vascular reactive oxygen species, and decreased nitric oxide production (4,22,23). Such mechanisms are observed in animal models when mineralocorticoid pathway activation is associated with nephrectomy and salt excess, ischemia, or pressure overload (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…MR is typically expressed in kidney cells, in which aldosterone/MR signaling regulates sodium reabsorption (1,2). MR is also present in the vasculature (endothelial and smooth muscle cells), where it contributes to the control of vascular tone (3,4). The retina also has mineralocorticoid target cells.…”

Section: Introductionmentioning

confidence: 99%

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Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Zhao

Célérier²,

Bousquet³

et al. 2012

J. Clin. Invest.

337

306

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Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Zhao

Célérier²,

Bousquet³

et al. 2012

J. Clin. Invest.

337

306

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“…Endothelial cells are involved in the induction of vascular calcification, and aldosterone has detrimental effects on the endothelium and the vasculature (40,41). Aldosterone downregulates eNos, an effect reversed by spironolactone (30).…”

Section: Figurementioning

confidence: 99%

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

et al. 2013

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Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH) 2 D 3 ] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH) 2 D 3 , FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.

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“…Lately, studies have demonstrated the presence of mineralocorticoid receptors (MR) in nonepithelial tissues, including heart and blood vessels (42). Aldosterone was reported to contribute to vascular remodeling and endothelial dysfunction through several coupling mechanisms (8,13,23), all associated with heightened vascular tone. Paradoxically, the increase in aldosterone levels in pregnancy occurs together with decreased vascular resistance (10), indicating that gestation resets some of the physiological responses normally consequent to an enhanced RAA system.…”

mentioning

confidence: 99%

Mineralocorticoids participate in the reduced vascular reactivity of pregnant rats

Provencher

Houde

Brochu

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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The renin-angiotensin-aldosterone (RAA) system is markedly activated in pregnancy. We evaluated if mineralocorticoid receptors (MR), a major component of the RAA system, are involved in the reduced vascular reactivity associated with pregnancy. Canrenoate (MR antagonist; 20 mg·kg Ϫ1 ·day Ϫ1 ) was administered to nonpregnant (NP) rats for 7 days and to pregnant rats from day 15 to 22 of gestation. These were killed on day 17, 19, or 22 of gestation and, for NP rats, after 7 days treatment. Constrictor responses to phenylephrine (PhE) and KCl were measured in endothelium-denuded thoracic aortic rings under the influence of modulators of potassium (activators) and calcium (blocker) channels. Responses to the constrictors were blunted from days 17 to 22 of gestation. Although canrenoate increased responses to PhE and KCl, it did not reverse their blunted responses in gestation. NS-1619 and cromakalim (respectively, highconductance calcium-activated potassium channels and ATP-sensitive potassium channel activators) diminished responses to both PhE and KCl. Inhibition by NS-1619 on responses to both agonists was decreased under canrenoate treatment in NP, but the reduced influence of NS-1619 during gestation was reversed by the mineralocorticoid antagonist. Cromakalim reduced the response to PhE significantly in the pregnant groups; this effect was enhanced by canrenoate. Finally, nifedipine (calcium channel blocker) markedly reduced KCl responses but to a lesser extent at the end of pregnancy, an inhibiting effect that was increased with canrenoate treatment. These data demonstrate that treating rats with a MR antagonist increased vascular reactivity but that it differentially affected potassium and calcium channel activity in aortas of NP and pregnant animals. This suggests that aldosterone is one of the components involved in vascular adaptations to pregnancy. potassium canrenoate; renin angiotensin aldosterone system; voltagedependent calcium channels; ATP-sensitive potassium channels; highconductance calcium-activated potassium channels IN HUMANS, arterial blood pressure (BP) decreases early in pregnancy, reaching a nadir during the second trimester (10, 26), whereas in rats it is stable until day 17 of gestation to decline gradually until term (day 23) (4, 37). This BP reduction is consequent to reduced vascular peripheral resistance associated with decreased influence of vasoconstrictor stimuli (3, 9, 10, 34, 37). These changes occur despite increases in blood volume and cardiac output and activation of the renin-angiotensin-aldosterone (RAA) system (2, 10, 39). In humans, by the sixth week of gestation, plasma renin activity (PRA) and aldosterone levels are already elevated and rise until term (10).In pregnant rats, PRA is increased early in gestation while aldosterone levels raise from midpregnancy until term (7, 18). In conditions other than pregnancy, such increases of the RAA system are associated with hypertension. This renders paradoxical the role of heightened RAA system in pregnancy (36).We have report...

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Mineralocorticoid receptors in vascular function and disease

Cited by 153 publications

References 125 publications

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

Mineralocorticoids participate in the reduced vascular reactivity of pregnant rats

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