The Mineralocorticoid Receptor: Insights into its Molecular and (Patho)Physiological Biology

Viengchareun, Say; Menuet, Damien Le; Martinerie, Lætitia; Munier, Mathilde; Tallec, Laurent Pascual-Le; Lombès, Marc

doi:10.1621/nrs.05012

Cited by 262 publications

(233 citation statements)

References 183 publications

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“…30 Accordingly, the predominant nuclear localization of the MR in the parathyroid cells of patients without PA ( Figure S1A, S1B, and S1D) suggests a role also of normal plasma levels of aldosterone in tonically regulating PTH secretion ( Figure S3). …”

Section: Discussionmentioning

confidence: 91%

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

et al. 2011

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P rimary aldosteronism (PA) is a common cause of secondary hypertension, because it involves 11.2% of referred hypertensive patients. 1 Primary hyperparathyroidism (PPTH) is much less common, with a prevalence that, albeit imprecisely known, is probably Ͻ0.01% in unselected hypertensives. However, arterial hypertension develops in the majority (56% to 80%) of the PPTH patients, 2 which can explain why they are held to be at increased risk for cardiovascular complications and death. 3 The association of PPTH with arterial hypertension and increased cardiovascular risk would appear to be paradoxical, inasmuch as the parathyroid hormone (PTH) has been described to induce vasodilation through endothelium-independent mechanisms. 4 Therefore, it would be expected to lower rather than to raise blood pressure. 5 The mechanisms by which excess PTH increases blood pressure remained obscure until Mazzocchi et al 6 reported that PTH stimulates in vitro the secretion of aldosterone from human adrenocortical cells in a concentrationdependent manner. These findings suggested that PTH acts as an aldosterone secretagogue that might be involved in causing human PA. However, whether this mechanism, although appealing, could be involved in causing human PA and might explain the development of arterial hypertension in patients with PPTH remained unsupported by any clinical data.We herein report on a patient who presented with resistant arterial hypertension and was found to have PA. Unilateral adrenalectomy resulted in cure of the PA and control of blood pressure despite a tapering of antihypertensive treatment, but the patient developed hyperparathyroidism caused by a PTHsecreting adenoma that was surgically removed. Gene expression and immunohistochemistry studies unveiled the expression of type 1 PTH receptor in the aldosterone-producing adrenocortical nodules and of the mineralocorticoid receptor (MR) in the nuclei of parathyroid adenoma cells. This latter finding was confirmed in a series of normal human parathyroid glands. Thus, this unique case and the related findings support the notion that undetected hyperfunctioning of the parathyroid gland can contribute to maintaining hyperaldosteronism in PA. It also suggests the existence of a bidirectional link between the adrenocortical zona glomerulosa and the parathyroid gland, which can be relevant for the regulation of calcium metabolism and blood pressure. CaseA 68-year-old man was referred for chest pain and resistant hypertension (Figure 1). The patient had a 10-year history of hypertension, which had become resistant to therapy with atenolol at 100 mg, amlodipine at 10 mg, doxazosin at 4 mg, potassium canrenoate at 25 mg, hydrochlorothiazide at 12.5 mg, and telmisartan at 80 mg daily. He had a family history of primary (essential) hypertension and a personal history of previous cigarette smoking, dyslipidemia, paroxysmal atrial fibrillation, and coronary artery disease that was treated with percutaneous transluminal coronary angioplasty and stenting 2 years before. Physical...

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Section: Discussionmentioning

confidence: 91%

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

et al. 2011

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“…[27][28][29] Aldosterone receptors are present in glomerular endothelial and epithelial cells, and in experimental animal models aldosterone infusion can cause direct injury to glomerular epithelial cells, leading to proteinuria and glomerulosclerosis. 30 These effects are believed to be mediated, in part, by upregulation of plasminogen activator inhibitor-1, TGF-␤, serum-and glucocorticoid regulated kinase 1, and NADPH oxidase and downregulation of nitric oxide. 31 The exact mechanism by which spironolactone reduces proteinuria in humans has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

Mehdi

Adams‐Huet²,

Raskin³

et al. 2009

Journal of the American Society of Nephrology

339

234

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Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio Ն300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, Ϫ51.0%, Ϫ11.2%, P ϭ 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, Ϫ37.3%, ϩ10.5%, P ϭ 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial. 20: 264120: -265020: , 200920: . doi: 10.1681 Diabetic nephropathy is the leading cause of ESRD worldwide. 1 The presence of nephropathy in diabetes is associated not only with excessive cardiovascular risk but also with increased risk for progression to ESRD. 2,3 It is well established that suboptimal BP control, activation of the renin-angiotensin-aldosterone system (RAAS), and proteinuria are important factors in the progression of diabetic nephropathy. Intensive BP lowering and administration of drugs that block the RAAS, such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), can slow progression of diabetic nephropathy. 4 -11 Renoprotection afforded by these agents is linked strongly and inextricably to reduction in proteinuria. Moreover, residual proteinuria is a strong predictor of adverse renal outcomes in long-term studies of patients treated with either an ACEi or an ARB. 7,12,13 Unfortunately, renoprotection afforded by J Am Soc Nephrol

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“…120 Finally, it has been shown that aldosterone induces a G6PD-deficient phenotype that can be improved by aldosterone antagonist or gene transfer of G6PD. 121 Of great interest, it has recently been suggested that, similar to what has been described in the heart, brain and vasculature, 122 the eye has a dynamic aldosterone-mineralocorticoid receptor system that has an important pathophysiological role in the development of retinal pathology. Wilkinson-Berka et al 123 , using a rat model of oxygen-induced retinopathy (OIR) that has features of premature retinopathy in humans with neovascularization, have shown that mineralocorticoid receptor antagonism with spironolactone improves retinal angiogenesis by attenuating leukostasis and decreasing proinflamatory responses.…”

Section: Role Of Renin-ang Aldosterone System With Emphasis On Aldostmentioning

confidence: 96%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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The Mineralocorticoid Receptor: Insights into its Molecular and (Patho)Physiological Biology

Cited by 262 publications

References 183 publications

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

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