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 recently developed non-steroidal MRA including finerenone, esaxerenone and balcinrenone are in early clinical use. It is not known if these MRA similarly modulate aldosterone-mediated gene expression. This study compares the effects of five MRA on the aldosterone-induced transcriptomic profile in two MR-expressing cell lines.
MCF7-MR (doxycycline-inducible MR expression) and MR+HEK293 (MR stably transfected) cells were treated with vehicle or aldosterone (3 nM in MCF7, 10 nM in HEK293), and either spironolactone (1 µM), eplerenone (5 uM), esaxerenone (1 µM), finerenone (1 µM) or balcinrenone (5 µM) for 4 hours. RNA sequencing results were evaluated for differentially expressed genes (DEG) with >1.5-fold change and <0.05 false discovery rate, using laxy.io and degust from Monash Bioinformatics.
In the MCF7 cells, we identified 167 DEG following any MRA treatment combined with aldosterone compared to aldosterone alone, including established MR target genes, SGK1 and PDK4. The remaining genes represent potential novel MR-regulated genes. There were also distinct DEG modulated by different MRA. For example, aldosterone-induced OTULINL expression was completed inhibited by esaxerenone and finerenone, but only partially by spironolactone and eplerenone; while aldosterone-induced STON2 expression was selectively repressed by esaxerenone without significant effect from the other MRA. In the HEK293 cells, there were 3 DEG with eplerenone and aldosterone compared to aldosterone alone, but no DEG with the other MRA alone or in combination with aldosterone.
It is often assumed that drugs within the same class would be equal in their actions. However, our study demonstrates that at least at a transcriptomic level, not all MRA are the same. This may have implications for their clinical effectiveness and adverse effect profiles.