The mineralocorticoid receptor (MR) is a high-affinity corticosteroid receptor that is central to electrolyte and fluid homeostasis via actions in epithelial tissues (kidney and colon). The MR is a known regulator of cardiac and renal tissue remodelling and failure and MR antagonists (MRA) such as spironolactone are now one of the four pillars of therapy for heart failure. MRA also show benefits for chronic kidney disease (CKD). However, steroidal MRAs are limited by adverse effects including hyperkalemia and renal impairment. Non-steroidal MRAs (e.g., finerenone, esaxerenone)are now available and are proposed to have improved safety profiles.
The MR is widely expressed in non-epithelial tissues including the inflammatory cells, adipose tissue, brain and skin, where its actions are highly context dependent. Emerging research reveals novel molecular mechanisms of MR regulation, including ligand-responses, transcriptional coregulators and MR-specific DNA binding sequences. Our recent work using a series of transgenic animal models identified bidirectional regulation between MR and the molecular circadian clock in cardiac and inflammatory cells and identified time-of-day-dependent MR modulation of clock genes (Per2, Cry1, REV-ERB⍺), inflammatory mediators (NOS2, IL-1β, CCL2), and metabolic regulators with sex-specific differences. Aldosterone and corticosterone were shown to directly influence clock gene oscillations in bone marrow-derived cells and cardiomyoblast cells. These findings suggest MR contributes to temporal regulation of inflammation and other cell functions and may underlie sex-based differences in cardiovascular disease. This presentation will explore MR signalling in the heart and inflammatory cells, its integration with circadian biology, and implications for MR-targeted therapies.