Epidermal Mineralocorticoid Receptor inactivation affects the homeostasis of all skin layers in chronologically aged mice.

ABSTRACT The endogenous increased production of glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacological treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We demonstrated that epidermal MR plays non-redundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated. 13-month old MR epidermal KO (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 SMAD2/3 activity. Importantly, the dermal white adipose tissue (dWAT) was 2.5-fold enlarged in 13-month MREKO vs 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. Also, 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.