Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity-When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

Abstract

The mineralocorticoid receptor (MR) is a member of the steroid receptor family and acts as a ligand-dependent transcription factor. In addition to its classical effects on water and electrolyte balance, its involvement in the pathogenesis of cardiovascular and renal diseases has been the subject of research for several years. The molecular basis of the latter has not been fully elucidated, but an isolated increase in the concentration of the MR ligand aldosterone or MR expression does not suffice to explain long-term pathologic actions of the receptor. Several studies suggest that MR activity and signal transduction are modulated by the surrounding microenvironment, which therefore plays an important role in MR pathophysiological effects. Local changes in micromilieu, including hypoxia, ischemia/reperfusion, inflammation, radical stress, and aberrant salt or glucose concentrations affect MR activation and therefore may influence the probability of unphysiological MR actions. The surrounding micromilieu may modulate genomic MR activity either by causing changes in MR expression or MR activity; for example, by inducing posttranslational modifications of the MR or novel interaction with coregulators, DNA-binding sites, or non-classical pathways. This should be considered when developing treatment options and strategies for prevention of MR-associated diseases.

Keywords: aldosterone; cardiovascular aging; hyperglycemia; hypoxia; inflammation; micromilieu; mineralocorticoid receptor.

Figure 1

Prior to ligand binding, the mineralocorticoid receptor (MR) is located in the cytoplasm. Its conformation is stabilized by different heat shock proteins (Hsp) and immunophilins. Upon binding of its ligand aldosterone, the receptor is translocated to the nucleus. The MR is also able to bind the glucocorticoid cortisol. In the nucleus, the receptor either homodimerizes with another ligand-bound MR or heterodimerizes with the glucocorticoid receptor (GR) and binds to the hormone response element (HRE), thereby enabling expression of MR target genes. Similarly to other steroid receptors, the MR recruits several coregulators that enhance or repress MR-induced gene expression. MR stability, activity, and signaling are regulated by various posttranslational modifications (PTMs), such as ubiquitination, sumoylation, phosphorylation, acetylation, and oxidation. Micro-RNAs (miR) are able to negatively regulate the expression of the MR as well as several MR target genes. The MR is involved in various pathologies affecting the kidney, central nervous system (CNS), adipose tissue, and, most importantly, the cardiovascular system. These pathologies cannot be exclusively attributed to changes in MR expression or aldosterone concentration. An altered cellular micromilieu due to inflammation, ischemia/hypoxia, oxidative stress, high salt intake, or elevated glucose concentrations can also affect MR signaling. These micromilieu changes can influence the expression of or interaction with several coregulators, miRs, and enzymes responsible for different PTMs, thereby contributing to pathological MR effects.