Mineralocorticoid receptor antagonists (MRA) have a central role in treating MR-mediated cardiovascular and renal conditions, including primary aldosteronism, resistant hypertension, heart failure and nephropathy. Steroidal MRA, spironolactone and eplerenone, are widely used, while non-steroidal MRA including finerenone, esaxerenone and balcinrenone are in early clinical use. It remains unclear whether these MRA exert equivalent effects on aldosterone-mediated gene expression.
This study aims to compare the transcriptomic effects of five MRAs on aldosterone-induced gene expression in an MR-expressing cell line.
MCF7 cells with doxycycline-inducible MR expression were treated with vehicle or aldosterone (3nM), with or without spironolactone (1µM), eplerenone (5µM), esaxerenone (1µM), finerenone (1µM) or balcinrenone (5µM) for 4 hours. RNA sequencing identified differentially expressed genes (DEG) with >2.0-fold change and <0.05 false discovery rate. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to validate selected DEGs, and dose-response studies were performed across five concentrations of each MRA.
DEGs were grouped as: 1) MRA-reversed aldosterone-induced upregulation (103 genes), 2) MRA-reversed aldosterone-induced downregulation (14 genes) and 3) MRA-regulated. Some genes were similarly modulated by all MRAs, while others showed divergent responses. For example, non-steroidal MRAs (finerenone and esaxerenone) fully reversed aldosterone-mediated downregulation of AMIGO2 and TNFRSF11B, whereas steroidal MRAs did not achieve full reversal, even at maximal doses.
Although MRAs are often considered interchangeable, our transcriptomic analysis reveals distinct gene regulatory profiles between the different MRAs. These findings suggest that not all MRAs are equal in their molecular actions, which may underlie differences in clinical efficacy and adverse effect profiles.