Clinical implications of mineralocorticoid receptor overactivation.

Abstract

The mineralocorticoid receptor (MR) is a nuclear transcription factor that plays a critical role in regulating fluid, electrolytes, blood pressure, and hemodynamic stability. In conditions such as chronic kidney disease (CKD) and heart failure (HF), MR overactivation leads to increased salt and water retention, inflammatory and fibrotic gene expression, and organ injury. The MR is essential for transcriptional regulation and is implicated in metabolic, proinflammatory, and pro-fibrotic pathways. It is widely expressed in various cell types throughout the body, including the gastrointestinal tract, heart, brain, kidneys, immune cells, and vasculature. Animal studies suggest that MR activation induces oxidative stress in the kidneys and mediates renal inflammation and fibrosis. Immune cell-specific deletion of MR has shown protection against cardiac fibrosis, indicating the MR's role in pathological remodeling. In vascular smooth muscle cells, the MR regulates vascular tone and vasoconstriction. Mineralocorticoid receptor antagonists (MRAs) can be categorized based on their chemical structure as either steroidal or nonsteroidal. Steroidal MRAs (sMRA), such as spironolactone and eplerenone, have demonstrated cardiovascular benefits but are limited by hyperkalemia, gynecomastia, and sexual dysfunction. Nonsteroidal MRAs (nsMRA) have shown promise in preclinical studies and clinical trials. They offer a promising alternative by effectively blocking MR without hormone-like effects, potentially improving cardiovascular and renal disease management. Further education is necessary regarding the significance of MRA utilization in CKD and HF, balancing benefits with the risk of hyperkalemia. This risk could be mitigated by combining MRAs with potassium-binding agents. Studies are underway to explore the synergistic effects between nsMRAs and other agents, such as SGLT-2i inhibitors and Glucagon-like peptide-1 agonists, to optimize cardiorenal outcomes. Overall, MR overactivation remains a significant therapeutic target, with nsMRAs showing promise as pivotal therapies in CKD and HF management. This review highlights the evolving landscape of MR-targeted therapies, their molecular mechanisms, and clinical implications in cardiorenal diseases.