Disease relevance of Nr3c2

• Due to their MR deficiency and the consecutive reduction of ENaC activity these mice die as neonates, and even after appropriate substitution therapy adult MR knockout mice suffer from high Na+ loss and hyperkalemia [1].
• To analyze in situ the effects of mineralocorticoid receptor (MR) on the nucleo-protein organization of the target MMTV promoter, we have established a new cell line by integrating in CV-1 cells a construct containing the long terminal repeat of the mouse mammary tumor virus (MMTV-LTR) [2].
• Targeted disruption of mineralocorticoid receptor (MR) gene results in pseudohypoaldosteronism type I with failure to thrive, severe dehydration, hyperkalemia, hyponatremia, and high plasma levels of renin, angiotensin II, and aldosterone [3].
• It was concluded the inner ear mineralocorticoid receptor is a significant target of glucocorticoids and a factor that should be considered in therapeutic treatments for steroid-responsive hearing loss [4].
• Thus, reducing systemic autoimmune disease was not sufficient to control hearing if mineralocorticoid receptor-mediated functions were blocked [4].

Psychiatry related information on Nr3c2

• These MR-related alterations may participate in the pathogenesis of hippocampal changes observed in ageing, chronic stress and affective disorders [5].
• For this purpose, the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation [6].
• This is the first detailed study of the ontogeny of these two genes and, in combination with previous work on the ontogeny of 11beta-HSD2 and the mineralocorticoid receptor, suggests potential critical periods of glucocorticoid sensitivity during development for several organ systems [7].

High impact information on Nr3c2

• Abnormal transcription factor induction through the surface immunoglobulin M receptor of B-1 lymphocytes [8].
• Aldosterone is a major regulator of salt balance and blood pressure, exerting its effects via the mineralocorticoid receptor (MR) [9].
• Our data broaden the known functions of aldosterone and suggest a potential role for MR in adipocyte differentiation and regulation of thermogenesis [9].
• To assess the function of the limbic MR in these processes, we inactivated the MR gene in the forebrain of the mouse using the Cre/loxP-recombination system [10].
• Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene [11].

Chemical compound and disease context of Nr3c2

• Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients [12].
• METHODS AND RESULTS: Ischemia was induced by right femoral artery ligature in mice treated or not with aldosterone (4.5 microg/day), aldosterone plus spironolactone (aldosterone receptor blocker; 20 mg/kg per day), or aldosterone plus valsartan (angiotensin type 1 [AT1] receptor blocker; 20 mg/kg per day) [13].
• Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney [14].
• Progesterone treatment caused a 2.5-fold increase in activity of the MR promoter in transiently transfected N2A neuroblastoma cells [15].
• Pharmacologic treatments that selectively target the mineralocorticoid receptor may provide greater clinical benefit with fewer systemic side effects than prednisone in patients with autoimmune sensorineural hearing loss [16].

Biological context of Nr3c2

• The regulation of ENaC expression was the same in both genotypes and thus irrespective of the presence of MR [1].
• The absence of GR in the host cell line allows the selective analysis of transcription activation by aldosterone in cells expressing MR transiently [2].
• The MMTV-LTR contains glucocorticoid response elements (GREs), known to interact with MR [2].
• This suggested both steroids are preserving hearing through the mineralocorticoid receptor within the ear to regulate endolymph homeostasis [4].
• Impairment of mineralocorticoid receptor (MR)-dependent biological response by oxidative stress and aging: correlation with post-translational modification of MR and decreased ADP-ribosylatable level of elongating factor 2 in kidney cells [17].

Anatomical context of Nr3c2

• Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice [5].
• The mineralocorticoid receptor may compensate for the loss of the glucocorticoid receptor at specific stages of mammary gland development [18].
• Thus, this new cell line M8, provides a useful tool for selectively studying the effect of MR on a target promoter organized into chromatin [2].
• Transient transfection assays in COS-1 cells showed that Ubc9 increased MR transactivation of reporter constructs containing MRE, ENaC, or MMTV promoter in a hormone-sensitive manner [19].
• Recently, interest in the roles of central nervous system mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) has increased [20].

Associations of Nr3c2 with chemical compounds

• Furthermore, adult MR-/- mice exhibited a significant reduction of granule cell neurogenesis to 65% of control levels, possibly mediated by GR due to elevated corticosterone plasma levels [5].
• Epithelial Na+ channel (ENaC) activity in kidney and colon is stimulated by aldosterone acting on the mineralocorticoid receptor (MR) [1].
• There must be subtle sequence differences that can account for the MR-specific binding of aldosterone and the shared binding of cortisol [21].
• The fractional occupancy of MR and GR by aldosterone mediating the sodium transport response in the aldosterone-sensitive distal nephron cannot be studied in vivo [22].
• This effect could not be blocked by antagonists of the mineralocorticoid receptor and glucocorticoid receptor (spironolactone and RU 38486, respectively) [23].

Regulatory relationships of Nr3c2

• The mineralocorticoid receptor antagonist spironolactone inhibited AngII-induced increases in NADPH oxidase activity and the increase in interstitial fibrosis [24].

Other interactions of Nr3c2

• These studies suggest that MR may compensate for the absence of GR at some, but not at all stages of mammary gland development [18].
• Mineralocorticoid specificity is ensured by 11beta-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR [22].
• Aldosterone rapidly activates Src kinase in M-1 cells involving the mineralocorticoid receptor and HSP84 [25].
• Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling [26].
• CONCLUSIONS: Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME-mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME-induced cardiovascular injury [27].

Analytical, diagnostic and therapeutic context of Nr3c2

• To understand the role of glucocorticoid and mineralocorticoid signalling during development and in whole animal physiology, we have disrupted the mouse glucocorticoid and mineralocorticoid receptor gene by gene targeting [28].
• Levels of GR and MR mRNA were examined by in situ hybridization and high-resolution silver emulsion autoradiography [29].
• Indeed, chromatin immunoprecipitation assays demonstrated that endogenous MR, Ubc9, and SRC-1 were recruited to an endogenous ENaC gene promoter in a largely aldosterone-dependent manner [19].
• Using a specific polyclonal antiserum raised in rabbit against amino acids 1-23 of the mouse mineralocorticoid receptor (MR) we investigated the developmental profile of MR expression in the murine CNS by immunocytochemistry [30].
• Immunoprecipitation of the native MR from either partially purified or crude preparations of rat kidney cytosol with hMRsN, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver stain, demonstrated a major protein band with a mol wt of 116 kilodaltons [31].

References