Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease

Abstract

The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them. In addition, the MR is involved in the regulation of the renal peripheral clock. One of the most common comorbidities observed in patients with chronic kidney disease (CKD) is poor sleep quality. Patients with CKD experience sleep disturbances, including reduced sleep duration, sleep fragmentation, and insomnia. To date, no studies have specifically investigated the relationship between MR activation and CKD-associated sleep disturbances. However, in this review, we analyzed the environment that occurs in CKD and proposed two MR-related mechanisms that may be responsible for these sleep disturbances: the circadian clock disruption and the high levels of MR agonist observed in CKD.

Keywords: chronic kidney disease; circadian clock; mineralocorticoid receptor; sleep quality.

Figure 1

Hypothalamic–pituitary–adrenal (HPA) axis components and regulations. The delivery of corticotropin releasing hormone (CRH) by the hypothalamus to the pituitary gland induces the secretion of adrenocorticotropic hormone (ACTH). ACTH leads to the adrenal glands producing cortisol and aldosterone, which mediates negative feedback to the hypothalamus through the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR).

Figure 2

Circadian clock pathway. CLOCK: Circadian locomotor output cycles kaput, BMAL1: brain and muscle aryl hydrocarbon receptor nuclear-like 1, E-box: enhancer box, CRY: cryptochrome, PER: period circadian protein homolog, ROR: retinoid-related orphan receptor, REV-ERBα: reverse erythroblastosis virus α, CK1δ/ε: Casein Kinase 1 isoforms δ/ε, RRE: ROR response element.

Figure 3

Kidney function circadian coupling. Representation of the circadian time (black line) with the peak of Na+/K+ excretion, the peak of blood pressure, and the peak of adrenal hormone release. Adrenal hormones: cortisol and aldosterone.

Figure 4

Potential mechanisms by which chronic kidney disease (CKD)-associated mineralocorticoid receptor (MR) dysregulation may lead to sleep disturbances. (A) The electrolytic imbalance observed in CKD through the overactivation of the MR could disrupt the circadian clock, which controls sleep and the hypothalamic-pituitary-adrenal (HPA) axis. Then, the altered HPA axis could dysregulate non-REM sleep phase (NREM) and rapid eye movement sleep phase (REM). (B) Hyperaldosteronemia and hypercortisolemia associated with CKD could lead to sleep disturbances in two ways. On one hand, through the HPA dysregulation and the consequent over occupancy of the glucocorticoid receptor (GR). On the other hand, increased levels of cortisol and aldosterone, as well as HPA axis dysregulation, lead to overactivation of the central GR and MR and entrance into the SWS phase.SWS: Slow-Wave Sleep.