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

Julia Boix,Marilisa Citton,Brasilina Caroccia,Francesca Torresan,Gian Paolo Rossi,Maurizio Iacobone,Lisa M Sevilla,Paloma Pérez,Judit Bigas

doi:10.1038/s41598-017-16216-5

Abstract

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.

Highlights

Primary aldosteronism (PA) is a disease characterized by high aldosterone levels caused by benign adrenal tumors being the most frequent cause of secondary hypertension
This study demonstrates that high levels of aldosterone in PA patients correlate with skin anomalies and inflammatory features associated with abnormal GR/mineralocorticoid receptor (MR) activation in epidermal keratinocytes
Hematoxylin/eosin (H&E) staining of skin samples revealed that individuals with non-secreting tumors had normal tissue architecture featuring relatively well differentiated epidermis consisting in 4–5 cell layers with compact stratum corneum and little cellularity in the dermal compartment[24] (Fig. 1a, middle panel, H&E)

Summary

Introduction

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 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. Aldosterone plays its main physiological role by retaining sodium and water, and excreting potassium in the kidney via MR, the ancestor hormone receptor from which the other steroid receptors, including the glucocorticoid (GC) receptor (GR), have evolved[4,5] Both MR and GR belong to the nuclear receptor subfamily NR3C and act as ligand-dependent transcription factors, which modulate transcription on target genes by binding to identical GC regulatory elements (GREs)[6,7,8]. MR has high affinity for binding cortisol, which circulates at

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Conclusion