Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

10 páginas, 5 figuras. Supplementary material is linked to the online version of the paper at https://doi.org/10.1016/j.jid.2020.03.933
The increased production of endogenous glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacologic treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We reported that epidermal MR plays nonredundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated. A 13-month-old MR epidermal knockout (MREKO) mice showed differential features of aging relative to controls (CO) in all skin compartments. MREKO mice were resistant to age-induced epidermal atrophy but showed reduced dermal thickness, with decreased collagen deposition and decreased SMAD2 and 3 activity. Importantly, the dermal white adipose tissue (dWAT) was 2.5-fold enlarged in 13-month MREKO versus CO, featuring adipocyte hyperplasia and hypertrophy at least in part through early increases in Pparg. These changes correlated with compartment-specific alterations in GC signaling. In addition, conditioned medium from MREKO keratinocytes increased adipocyte differentiation, indicating paracrine regulation of adipogenesis through mechanisms that include activation of β-catenin signaling. These findings highlight the importance of epidermal MR in regulating cross-talk among skin compartments in naturally aged skin through GC and β-catenin signaling pathways.
This research was supported by grant SAF2017-880464-R (Ministerio de Economı´a y Competitividad [MINECO], Spanish Government). JB is a recipient of Formacio´n Personal Investigador fellowship from MINECO (BES2015- 072722). The authors thank MINECO Nuclear Receptors in Cancer, Metabolism, and Inflammation for Networks of Excellence grant (SAF2017-90604-REDT).