Context-dependent mechanisms modulating aldosterone signaling in the kidney

The aldosterone-mineralocorticoid receptor (MR) system serves as the major regulator of fluid homeostasis, and is an important drug target for the treatment of hypertension, heart failure, and chronic kidney disease. While the ligand aldosterone plays a central role in facilitating MR activity, recent studies have revealed that MR signaling is modulated through distinct mechanisms at the levels of the receptor and the downstream targets. Notably, phosphorylation of the ligand-binding domain in MR regulates the ability of the receptor to bind to ligand in renal intercalated cells, providing an additional layer of regulation that allows the cell-selective control of MR signaling. These mechanisms are involved in the context-dependent effects of aldosterone in the distal nephron. In this article, the recent progress in the understanding of mechanisms regulating the action of aldosterone is discussed, focusing on the connecting tubules and collecting duct in the kidney.