Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

Bauersachs, Johann; Jaisser, Frédéric; Toto, Robert D.

doi:10.1161/hypertensionaha.114.04488

Cited by 186 publications

(160 citation statements)

References 83 publications

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“…These findings are consistent with clinical studies demonstrating that besides the classical use of MR antagonists for treating hypertension, pharmacological blockade of MR was also beneficial for patients suffering from other inflammatory and fibrotic diseases (Jaisser and Farman, 2016). The mechanisms mediating pathological MR activation include activation of the NF-B pathway and oxidative stress as well as upregulation of MR-targets including pro-fibrotic genes (Bauersachs et al, 2015).…”

Section: Introductionsupporting

confidence: 85%

091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

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et al. 2016

Journal of Investigative Dermatology

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Glucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases, however, adverse effects of chronic GC treatments limit their therapeutic use.GCs bind and activate the GC receptor (GR) and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements (HREs).Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knock-out (MR EKO ) mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR EKO mice showed increased susceptibility to PMA-induced inflammation with higher cytokine induction.Likewise, cultured MR EKO keratinocytes had increased PMA-induced NF-B activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR EKO keratinocytes, at least partially due to decreased recruitment of GR to HRE-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate non-redundant roles for MR and GR in mediating GC actions.3

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Section: Introductionsupporting

confidence: 85%

091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

Tarín

Sevilla

Sáez

et al. 2016

Journal of Investigative Dermatology

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“…58 MR is, therefore, a key therapeutic target for cardiac and renal target-organ damage in hypertension and may prevent diastolic dysfunction and heart failure development. 59,60 Indeed, MR knockout prevents development of diet-induced diastolic dysfunction. 61 Interestingly, some effects of aldosterone seem to involve angiotensin type 1a receptors.…”

Section: Mineralocorticoid Receptors In the Regulation Of Oxidative Smentioning

confidence: 99%

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

2017

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Figure.Central role of oxidative stress in accelerated vascular aging in hypertension. AT1R indicates angiotensin II receptor type 1; BH 2 , dihydrobiopterin; BH 4 , tetrahydrobiopterin; BMP, bone morphogenic protein; CypD, cyclophilin D; eNOS, endothelial NO synthase; ET1R, endothelin 1 receptor; H 2 O 2 , hydrogen peroxide; MMP, matrix metalloproteinase; Nox, NADPH oxidase; O 2 −. , superoxide anion; RANTES, regulated on activation, normal T cell expressed and secreted chemokine; and SmgGDS, GTP-binding protein dissociation stimulator. by guest on

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“…53 MR activation leads to an upregulation of proinflammatory cytokines and profibrotic proteins, such as transforming growth factor β or plasminogen activator inhibitor 1.…”

Section: Doca/salt-induced Kidney Injury Is Independent From Endothelmentioning

confidence: 99%

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

et al. 2016

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Abstract-Chronic kidney disease has a tremendously increasing prevalence and requires novel therapeutic approaches.Mineralocorticoid receptor (MR) antagonists have proven highly beneficial in the therapy of cardiac disease. The cellular and molecular events leading to cardiac inflammation and remodeling are proposed to be similar to those mediating renal injury. Thus, this study was designed to evaluate and directly compare the effect of MR deletion in endothelial cells on cardiac and renal injury in a model of deoxycorticosterone acetate-induced hypertension. Endothelial MR deletion ameliorated deoxycorticosterone acetate/salt-induced cardiac remodeling. This was associated with a reduced expression of the vascular cell adhesion molecule Vcam1 in MR-deficient cardiac endothelial cells. Ambulatory blood pressure telemetry revealed that the protective effect of MR deletion was independent from blood pressure. Similar to the heart, deoxycorticosterone acetate/salt-induced severe renal injury, including inflammation, fibrosis, glomerular injury, and proteinuria. However, no differences in renal injury were observed between genotypes. In conclusion, MR deletion from endothelial cells ameliorated deoxycorticosterone acetate/salt-induced cardiac inflammation and remodeling independently from alterations in blood pressure but it did not affect renal injury. These findings suggest that the anti-inflammatory mechanism mediating organ protection after endothelial cell MR deletion is specific for the heart versus the kidney.

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Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

Cited by 186 publications

References 83 publications

091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

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