The mineralocorticoid receptor (Nuclear receptor subfamily 3 group C member 2, NR3C2) is a receptor with equal affinity for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. NR3C2 is expressed in many tissues such as kidney, heart, the CNS and sweat glands. Its activation leads to the expression of proteins regulating ionic and water transport resulting in the reabsorption of sodium. Consequently, there is an increase in extracellular volume, an increase in blood pressure, and increased excretion of potassium to maintain normal salt concentrations.

Synthetic NR3C2 antagonists competitively inhibit NR3C2 (Kagawa et al. 1957, Pollow et al. 1992, Rupprecht et al. 1993) in the kidney distal convoluted tubule to promote sodium and water excretion and potassium retention. These diuretic drugs are typically indicated for congestive heart failure, hypertension and chronic kidney disease. Synthetic antagonists of NR3C2 include the steroidal compounds spironolactone, eplerenone, and drospirenone. Nimodipine, a calcium channel blocker, can also act as an NR3C2 antagonist (Dietz et al. 2008, Luther 2014).

The broad clinical use of steroidal mineralocorticoid receptor antagonists is limited by the potential risk of inducing hyperkalemia. Novel, non-steroidal NR3C2 antagonists demonstrate an improved therapeutic index for hyperkalemic risk compared to their steroidal counterparts in preclinical models (reviews Kolkhof et al. 2015, Kolkhof & Bärfacker 2017, Sueta et al. 2020). Compounds undergoing clinical trials include apararenone (no trial data), esaxerenone (Arai et al. 2015), and finerenone (Bärfacker et al. 2012, Amazit et al. 2015).

Fludrocortisone is a synthetic mineralocorticoid used in conjunction with hydrocortisone to replace missing endogenous corticosteroids in patients with adrenal insufficiency. It is functionally similar to aldosterone, the body's primary endogenous mineralocorticoid, and is structurally analogous to cortisol, differing only by a fluorine atom at the 9-position of the steroid structure and having similar affinity for the mineralocorticoid receptor (NR3C2) as aldosterone (Rupprecht et al. 1993, Oelkers et al. 1994).

Fludrocortisone is indicated as partial replacement therapy for primary or secondary adrenocortical insufficiency in Addison's disease and for the treatment of salt-losing androgenital syndrome (Charmandari et al. 2014, Hamitouche et al. 2017). Fludrocortisone has also shown to be effective in the treatment of cerebral salt-wasting syndrome (Taplin et al. 2006, Misra et al. 2018). Common side effects of fludrocortisone include high blood pressure, swelling, heart failure, and low blood potassium.

Steroid hormones receptors (SHRs) are intracellular transcription factors that can be activated by binding specific ligands (i.e., steroid hormones (SH)) to the ligand-binding domain (LBD) (Ray DW et AL. 1999; Pike AC et al. 1999; Bledsoe RK et al. 2002; Li Y et al. 2005; Kumar R and McEwan IJ 2012; Kumar R et al. 2011; Williams SP & Sigler PB 1998; Tanenbaum DM et al. 1998; Lusher SJ et al. 2012). LBD (E-region) resides in the C-terminal half of the receptor and in addition to ligand binding function contains a transcriptional activation function (AF2), sequences for dimerization, heat shock protein association, intermolecular silencing and intramolecular repression (Kumar R and McEwan IJ 2012). The binding of hormone acts as an allosteric switch to regulate SHR-DNA and SHR-protein interactions, including interdomain interactions and/or dimerization (Kumar R and McEwan IJ 2012).

SHs are synthesized from cholesterol in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, estrogen), and the ovary and placenta (estrogen and progestogen or progestins) (Payne AH & Hales DB 2004; Hu J et al. 2010;). SHs reach their target cells via the blood, where they are bound to specific carrier proteins (Grishkovskaya I et al. 2000; Hammond GL 2016). SHs detach from the carrier proteins and because of their lipophilic nature readily diffuse through the plasma membrane of cells (Oren I et al. 2004). Within the target cells SHs bind to steroid hormone receptors (SHRs) which are present in a heterocomplex with heat shock protein HSP90 and co-chaperones (e.g., immunophilins p23) (Echeverria PC & Picard D 2010). The ATP-bound form of HSP90 and chaperone-mediated conformational changes are required to keep SHRs in a ligand binding-competent state (McLaughlin SH et al. 2002; Pratt WB et al. 2008; Krukenberg KA et al. 2011).

PIAS1 SUMOylates NR3C2 (Mineralcorticoid receptor, MR) at lysine-89, lysine-399, lysine-428, and lysine 494 with SUMO1 (Tallec et al. 2003, Tirard et al. 2007, Yokota et al. 2007). SUMOylation represses the transcription activation activity of NR3C2.