Protein Phosphatase 1α enhances renal aldosterone signaling via mineralocorticoid receptor stabilization

• PP1α is a novel cytoplasmic partner of MR that binds the receptor in absence of ligands.
• PP1α stabilizes MR expression by reducing MDM2 activation and MDM2-mediated MR proteasomal degradation.
• PP1α activity is required to maintain an appropriate response to aldosterone in renal epithelial cells.

Stimulation of the mineralocorticoid receptor (MR) by aldosterone controls several physiological parameters including blood pressure, inflammation or metabolism. We previously showed that MR turnover constitutes a crucial regulatory step in the responses of renal epithelial cells to aldosterone. Here, we identified Protein Phosphatase 1 alpha (PP1α), as a novel cytoplasmic binding partner of MR that promotes the receptor activity. The RT-PCR expression mapping of PP1α reveals a high expression in the kidney, particularly in the distal part of the nephron. At the molecular level, we demonstrate that PP1α inhibits the ubiquitin ligase Mdm2 by dephosphorylation, preventing its interaction with MR. This results in the accumulation of the receptor due to reduction of its proteasomal degradation and consequently a greater aldosterone-induced Na+ uptake by renal cells. Thus, our findings describe an original mechanism involving a phosphatase in the regulation of aldosterone signaling and provide new and important insights into the molecular mechanism underlying the MR turnover.