Endocrine Abstracts

Aldosterone exerts numerous pleiotropic functions, notably in the kidney where it controls hydroelectrolytic homeostasis and ultimately blood pressure. Aldosterone acts by activating the mineralocorticoid receptor (MR), a transcription factor that regulates target gene expression. Alteration of the mineralocorticoid signaling leads to various diseases including hypertension, cardiovascular, renal, metabolic or CNS disorders.

Aldosterone mechanism of action is extremely complex, involving several intricate aspects (1) whereby kinetic and cross-talk dynamics appeared to play a critical role in the control of transepithelial sodium transport. An overall assessment of MR genomic targets by new tools was therefore highly desirable. We setup the chromatin immunoprecipitation (ChIP) with a specific anti-MR antibody in highly differentiated human renal cells expressing GFP-MR. This approach coupled with the innovative high-throughput sequencing technology (ChiP seq, HiSeq) allowed identification of approximately one thousand direct genomic MR targets. Computational analysis of these genomic sites defined a specific MR response element (MRE) in which the AGtACAgxatGTtCt sequence was the most prevalent motif. Of interest, most genomic MR-binding sites (MBSs) (84%) are located at long distances (>10 kb and up to 150 kb) and various directions from the transcriptional start sites of corresponding target genes, either well-known or new mineralocorticoid-response genes. Specific aldosterone-induced recruitment of MR on genomic sequences was validated by ChIP-qPCR and correlated with concomitant and positive aldosterone-activated transcriptional gene regulation as assayed by RT-qPCR. Of note, most MBSs lacked MREs but harbored DNA recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5) suggesting functional interaction (2). Dynamics of MR recruitment and of its transcriptional co-regulators demonstrated that finerenone, a novel non-steroidal MR antagonist, prevents assembly of active transcriptional initiation complexes (3). These studies provide new insights into aldosterone, MR-mediated renal signaling. Many unanswered questions remain notably concerning specificity of corticosteroid receptor action yet opening germane perspectives for mineralocorticoid-related pathophysiology.