Mineralocorticoid Receptor Antagonists—A New Sprinkle of Salt and Youth

Stojadinović, Olivera; Lindley, Linsey E.; Jozic, Ivan; Tomic‐Canic, Marjana

doi:10.1016/j.jid.2016.07.025

Cited by 8 publications

(10 citation statements)

References 19 publications

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“…In contrast, MR blockades do not modify wound closure from normal mice. We propose that inadequate MR occupancy by exogenous glucocorticoid (GC) or locally produced GC, as well as enhanced MR expression, may explain the benefit of MR blockade in a variety of pathological situations such as dermocorticoid treatments, UV irradiation, diabetic delayed wound healing, and perhaps psoriatic skin or GC-treated psoriasis (Hannen et al, 2017;Stojadinovic et al, 2016). In addition, local steroidogenesis and modulation of 11b-hydroxysteroid dehydrogenase type 1 may interfere with MR/GC receptor signaling balance in skin diseases (Sevilla and Pérez, 2018;Slominski et al, 2014Slominski et al, , 2015Tiganescu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

Nguyen

Farman

Palacios

et al. 2020

Journal of Investigative Dermatology

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Skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Here, we report that topical pharmacological inhibition of the mineralocorticoid receptor (MR) by canrenoate or MR small interfering RNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected. The beneficial effect of canrenoate is associated with an increased ratio of anti-inflammatory M2 macrophages to proinflammatory M1 macrophages in diabetic wounds. Furthermore, we show that MR blockade leads to downregulation of the MR target, LCN2, which may facilitate macrophage polarization toward the M2 phenotype and improve impaired angiogenesis in diabetic wounds. Indeed, diabetic LCN2-deficient mice showed improved wound healing associated with macrophage M2 polarization and angiogenesis. In addition, recombinant LCN2 protein prevented IL-4einduced macrophage switch from M1 to M2 phenotype. In conclusion, topical MR blockade accelerates skin wound healing in diabetic mice via LCN2 reduction, M2 macrophage polarization, prevention of inflammation, and induction of angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

Nguyen

Farman

Palacios

et al. 2020

Journal of Investigative Dermatology

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“…Steroid hormones play key roles in skin homeostasis and inflammatory conditions 29 . Thus, understanding the relative roles of GR and MR, two closely related hormone receptors, in this tissue is increasingly becoming a focus of attention 14 , 19 , 20 . Although we have investigated the transcriptional function of GR and MR upon aldosterone treatment, we cannot rule out that some of the reported findings are due to a rapid pathway mediated through membrane GR or MR, or other unknown membrane receptors 10 .…”

Section: Discussionmentioning

confidence: 99%

Primary aldosteronism patients show skin alterations and abnormal activation of glucocorticoid receptor in keratinocytes

Boix

Bigas

Sevilla

et al. 2017

Sci Rep

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Primary aldosteronism (PA) is a disease characterized by high aldosterone levels caused by benign adrenal tumors being the most frequent cause of secondary hypertension. Aldosterone plays vital physiological roles through the mineralocorticoid receptor (MR) but in certain cell types, it can also activate the glucocorticoid (GC) receptor (GR). Both MR and GR are structurally and functionally related and belong to the same family of ligand-dependent transcription factors that recognize identical GC regulatory elements (GREs) on their target genes. GCs play key roles in skin pathophysiology acting through both GR and MR; however, the effects of aldosterone and the potential association of PA and skin disease were not previously addressed. Skin samples from PA revealed histopathological alterations relative to control subjects, featuring epidermal hyperplasia, impaired differentiation, and increased dermal infiltrates, correlating with increased NF-κB signaling and up-regulation of TNF-A and IL-6 cytokines. PA skin samples also showed significantly higher expression of MR, GR, and HSD11B2. In cultured keratinocytes, aldosterone treatment increased GRE transcriptional activity which was significantly inhibited by co-treatment with GR- and MR-antagonists. This study demonstrates that high levels of aldosterone in PA patients correlate with skin anomalies and inflammatory features associated with abnormal GR/MR activation in epidermal keratinocytes.

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“…Recent studies have highlighted that inappropriately activated MR caused by excess GC is involved in generating GC-mediated cutaneous side effects, such as delayed wound healing, epidermal atrophy, and skin aging. Furthermore, such side effects can be prevented by topical MR blockade 25 – 28 .…”

Section: Introductionmentioning

confidence: 99%

A novel mineralocorticoid receptor antagonist, 7,3',4'-trihydroxyisoflavone improves skin barrier function impaired by endogenous or exogenous glucocorticoids

Lee

Choi

Kim

et al. 2021

Sci Rep

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Excess glucocorticoids (GCs) with either endogenous or exogenous origins deteriorate skin barrier function. GCs bind to mineralocorticoid and GC receptors (MRs and GRs) in normal human epidermal keratinocytes (NHEKs). Inappropriate MR activation by GCs mediates various GC-induced cutaneous adverse events. We examined whether MR antagonists can ameliorate GC-mediated skin barrier dysfunction in NHEKs, reconstructed human epidermis (RHE), and subjects under psychological stress (PS). In a preliminary clinical investigation, topical MR antagonists improved skin barrier function in topical GC-treated subjects. In NHEKs, cortisol induced nuclear translocation of GR and MR, and GR and MR antagonists inhibited cortisol-induced reductions of keratinocyte differentiation. We identified 7,3’,4’-trihydroxyisoflavone (7,3’,4’-THIF) as a novel compound that inhibits MR transcriptional activity by screening 30 cosmetic compounds. 7,3’,4’-THIF ameliorated the cortisol effect which decreases keratinocyte differentiation in NHEKs and RHE. In a clinical study on PS subjects, 7,3',4'-THIF (0.1%)-containing cream improved skin barrier function, including skin surface pH, barrier recovery rate, and stratum corneum lipids. In conclusion, skin barrier dysfunction owing to excess GC is mediated by MR and GR; thus, it could be prevented by treatment with MR antagonists. Therefore, topical MR antagonists are a promising therapeutic option for skin barrier dysfunction after topical GC treatment or PS.

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Mineralocorticoid Receptor Antagonists—A New Sprinkle of Salt and Youth

Cited by 8 publications

References 19 publications

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

Primary aldosteronism patients show skin alterations and abnormal activation of glucocorticoid receptor in keratinocytes

A novel mineralocorticoid receptor antagonist, 7,3',4'-trihydroxyisoflavone improves skin barrier function impaired by endogenous or exogenous glucocorticoids

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