30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

Abstract

The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone. Generation of tissue-selective MR-deficient mice using Cre recombinase-LoxP gene targeting has made it possible to analyse mice lacking MR only in specific cell types. Targeting renal-specific MR has differentiated roles in specific compartments of the kidney. Ablating MR in neurons of the forebrain reinforced important roles of the MR in response to stress, behaviour and anxiety, but suggested a minimal role in maintaining basal HPA axis tone. Deletion of the MR in macrophages and other cell types of the cardiovascular system clearly defined important roles for the regulation of cardiovascular physiology and pathophysiology. Knockdown of MR mRNA in vivo using antisense/siRNA approaches, and similarly MR overexpression, has provided useful rodent models to study physiological roles of MR signalling in vivo. More recently, targeted mutation of specific domains of the MR such as the DBD has defined genomic vs non-genomic roles in vivo. New tissue-selective MR-null models are required to define roles of MR signalling in other regions of the brain, the eye, gastrointestinal tract, lung, skin, breast and gonadal organs.

Endothelial cell mineralocorticoid receptors oppose VEGF-induced gene expression and angiogenesis

“…In the cardiovascular system, MR is expressed in cardiac myocytes, fibroblasts, endothelial cells, smooth muscle cells and immune cells (Lother et al 2015, DuPont & Jaffe 2017. A series of studies using cell type-specific MR deletion models revealed distinct roles of MR in these different cell types for hypertension, atherosclerosis, myocardial infarction and heart failure and in particular found MR in endothelial cells to be a crucial player in cardiovascular disease (Lother et al 2015, Young & Rickard 2015, Cole & Young 2017. Activation of MR in endothelial cells impairs vascular reactivity (Schafer et al 2013, Rickard et al 2014, Barrett Mueller et al 2015, promotes inflammation (Jia et al 2015 and contributes to cardiac fibrosis and hypertrophy (Jia et al 2015.…”

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

“…Although these previous studies have clarified MR functions in the kidneys and cardiovascular tissues, the roles of MR in other epithelial tissues, such as the intestinal epithelium, have not been elucidated. MR is reportedly expressed throughout the intestine,22 and aldosterone increases the expression of the epithelial sodium channel (ENaC) in rats23; however, there are no studies focusing on the functions of MR in intestinal epithelial cells (IECs) using MR deletion mutants, the implementation of which is required 24. Furthermore, it is not clear how intestinal MR contributes to sodium dynamics and BP regulation.…”

Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

“…• Extra-adrenal production of aldosterone by aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity via intrinsic activation of neuronal mineralocorticoid receptors • Intrathecally-applied aldosterone synthase inhibitor reduced aldosterone content in peripheral sensory neurons and subsequently attenuated enhanced mechanical hypersensitivity resulting from local inflammation A ldosterone is known to regulate the body's water and electrolyte balance through activation of corresponding mineralocorticoid receptors on epithelial cells of the renal cortical collecting ducts leading to sodium and water retention in exchange for excreted potassium. 1,2 Aldosterone is generated and secreted in the zona glomerulosa of the adrenal gland through local aldosterone synthase (CYP11B2). 1 Aldosterone circulates in the blood unbound (30 to 50% of total aldosterone) or bound to albumin-or corticosteroid-binding globulin (50 to 70% of total aldosterone).…”

“…1,2 Aldosterone is generated and secreted in the zona glomerulosa of the adrenal gland through local aldosterone synthase (CYP11B2). 1 Aldosterone circulates in the blood unbound (30 to 50% of total aldosterone) or bound to albumin-or corticosteroid-binding globulin (50 to 70% of total aldosterone). It is rapidly inactivated in the liver with a plasma half-life of 15 to 20 min.…”