The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology

Abstract

The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated. Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders.

Figure 1. Schematic representation of human MR structure.

MR gene, mRNA, protein, functional domains and associated posttranslational modifications are depicted. The hMR gene is composed of ten exons, including two untranslated first exons (1α and 1β). The AUG translational initiation start codon is located 2 bp after the beginning of exon 2, while the stop codon is located in exon 9. Multiple mRNA isoforms generated by alternative transcription or splicing events are translated into various protein variants, including those generated by utilization of alternative translation initiation sites (not shown). The receptor is comprised of distinct functional domains (activation function AF-1a, AF-1b and AF-2) and nuclear localization signals (NLS0, NLS1 and NSL2), as well as one nuclear export signal (NES). The positioning of amino acids targeted for phosphorylation, sumoylation, acetylation and ubiquitylation is indicated for the human MR sequence.

Figure 2. Model of MR action in a renal polarized epithelial cell.

Aldosterone enters a target cell and binds MR, which translocates into the nucleus. MR interacts with a HRE, recruits various transcriptional coregulators (Coregulators) to activate the transcriptional machinery (TM), and thus alters expression of aldosterone target genes (in blue). At the apical membrane, ENaC (epithelial sodium channel), composed of three subunits (α, β and γ), constitutes the rate-limiting step of apical Na⁺ entry. Na⁺ is then extruded into the basolateral space by the Na⁺/K⁺-ATPase pump, the activity of which is modulated in the colon by the regulatory protein CHIF (corticosteroid hormone-induced factor). In the absence of aldosterone, ENaC proteins interact with Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. SGK1 (serum and glucocorticoid-regulated kinase) is a key aldosterone-regulated target gene that plays a central role in sodium reabsorption. Upon aldosterone exposure, PDK1-activated kinase SGK1 phosphorylates Nedd4-2, which in turn dissociates from ENaC, increasing its apical membrane abundance. Usp2-45, a novel early aldosterone-induced mRNA, is an ubiquitin-specific protease which deubiquitylates ENaC and thereby increases ENaC-mediated sodium transport. Other aldosterone-induced genes included kidney specific KS-WNK1 (serine/threonine kinase With No K), K-Ras2, NDRG2 (N-myc down-stream regulated gene 2), GILZ (glucocorticoid-induced leucine zipper), endothelin ET-1 and plasminogen activator inhibitor-1 (PAI-1).

Figure 3. Schematic localization of MR mutations causing pseudohypoaldosteronism type 1 and polymorphisms in the human NR3C2 gene.

Nucleotide and amino acid numbering is indicated in reference to the published cDNA, where +1 is the A of the translational initiation codon (Arriza et al., 1987). Fs, frameshift (red); X, stop codon (blue); missense (green); sp alt, splice alteration (purple); polymorphism (black).