Antagonistic effects of finerenone and spironolactone on the aldosterone‐regulated transcriptome of human kidney cells

Abstract

Aldosterone, the main mineralocorticoid hormone in humans, plays a pivotal role in the control of water and salt reabsorption via activation of the mineralocorticoid receptor (MR). Alterations in MR signaling pathway lead to renal dysfunction, including chronic kidney disease and renal fibrosis, that can be prevented or treated with mineralocorticoid receptor antagonists (MRAs). Here, we used RNA-Sequencing to analyze effects of two MRAs, spironolactone and finerenone, on the aldosterone-induced transcriptome of a human renal cell line stably expressing the MR.Bioinformatics analysis of the data set reveals the identity of hundreds of genes induced or repressed by aldosterone. Their regulation is modulated in a time-dependent manner and, for the induced genes, depends on the aldosterone-driven direct binding of the MR onto its genomic targets that we have previously characterized. Although both MRAs block aldosterone-induced as well as aldosterone-repressed genes qualitatively similarly, finerenone has a quantitatively more efficient antagonism on some aldosterone-induced genes. Our data provide the first complete transcriptome for aldosterone on a human renal cell line and identifies pro-inflammatory markers (IL6, IL11, CCL7, and CXCL8) as aldosterone-repressed genes.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…Le Billan et al investigated the effects of spironolactone and finerenone on the aldosterone-induced transcriptome of a human renal cell line stably expressing MR. They found similar gene expression profiles in both MRAs, but finerenone exerted more efficient antagonism on some aldosterone-induced genes ( Le Billan et al, 2021 ). • Clinical Studies …”

Evolution of Mineralocorticoid Receptor Antagonists in the Treatment of Chronic Kidney Disease Associated with Type 2 Diabetes Mellitus

“… 15 , 48 Spironolactone can be regarded as a prodrug with a short half-life (<2 hours) that generates 3 active metabolites with longer half-lives (>12-24 hours) ( Table 1 ). 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 Spironolactone may cause gynecomastia and impotence in males through its binding with the androgen receptor (AR) as an antagonist and menstrual irregularities and breast tenderness in women through its binding with the progesterone receptor (PR) as an agonist. 48 , 51 , 52 , 53 , 69 Research programs aimed at identifying more receptor-specific steroidal MRAs to decrease these side effects, led to the discovery of eplerenone.…”

“…Differences in molecular structure and MRA activity underpin the distinct effects of spironolactone and eplerenone observed in preclinical and clinical studies ( Table 1 ). 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 …”

“…Furthermore, RNA sequencing analyses showed that approximately 20% of transcripts induced by aldosterone were antagonized by finerenone, whereas, only 5% were antagonized by spironolactone. 60 Chromatin immunoprecipitation assays in the SCNN1A promoters suggest that although finerenone prevents the basal recruitment of the MR and steroid receptor coactivator 1 (SRC-1), spironolactone mildly promotes basal recruitment of these 2 regulators (aldosterone-dependent recruitment of the MR, SRC-1, and RNA polymerase II was also prevented by finerenone). 59 These results suggest that finerenone confers a more profound antagonistic effect on mineralocorticoid target genes than spironolactone.…”

Approaches towards tissue‐selective pharmacology of the mineralocorticoid receptor

“…Collectively, these transcriptomic profiling studies show that MR activation drives a pro‐inflammatory and profibrotic gene programme in nonepithelial cells, leading to adverse tissue remodelling and eventually organ failure (Figure 1). However, there is also an overlapping gene expression signature in response to MR activation between epithelial and nonepithelial cells, including FK506 binding protein 5 ( Fkbp5 ), period circadian regulator 1 ( Per1 ) and TSC22 domain family member 3 ( Tsc22d3 ) (Fletcher et al, 2017; Latouche et al, 2010; Le Billan et al, 2018, 2021; Lother et al, 2019; Sekizawa et al, 2011). Remarkably, several overlapping genes are not exclusively regulated by the MR but also by other nuclear receptors such as the GR and some even by the AR (Kulik et al, 2021; Mifsud & Reul, 2016), with serum and glucocorticoid‐regulated kinase 1 (SGK1), for example, being a prototypical shared MR/GR target gene (Le Billan et al, 2015; Mifsud & Reul, 2016; Pooley et al, 2020).…”