Mineralocorticoid receptor

Target not currently curated in GtoImmuPdb

Target id: 626

Nomenclature: Mineralocorticoid receptor

Systematic Nomenclature: NR3C2

Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Natural/Endogenous Ligands
Rank order lists
Agonists
Antagonists
DNA Binding
Co-binding Partners
Main Co-regulators
Main Target Genes
Tissue Distribution
Functional Assays
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
References
Contributors
How to cite this page

Gene and Protein Information
Species	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	984	4q31	NR3C2	nuclear receptor subfamily 3 group C member 2	2
Mouse	978	8 36.34 cM	Nr3c2	nuclear receptor subfamily 3, group C, member 2	3
Rat	981	19q11	Nr3c2	nuclear receptor subfamily 3, group C, member 2	79

Previous and Unofficial Names
aldosterone receptor \| Type I glucocorticoid receptor \| MCR \| MLR \| MR \| nuclear receptor subfamily 3

Previous and Unofficial Names

aldosterone receptor | Type I glucocorticoid receptor | MCR | MLR | MR | nuclear receptor subfamily 3

Database Links
Specialist databases
Transcriptomine	NR3C2&foldChange=1.6&direction=down, NR3C2&foldChange=1.75&direction=up
Other databases
Alphafold	P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
CATH/Gene3D	3.30.50.10
ChEMBL Target	CHEMBL1994 (Hs), CHEMBL3507 (Rn)
DrugBank Target	P08235 (Hs)
Ensembl Gene	ENSG00000151623 (Hs), ENSMUSG00000031618 (Mm), ENSRNOG00000034007 (Rn)
Entrez Gene	4306 (Hs), 110784 (Mm), 25672 (Rn)
Human Protein Atlas	ENSG00000151623 (Hs)
KEGG Gene	hsa:4306 (Hs), mmu:110784 (Mm), rno:25672 (Rn)
OMIM	600983 (Hs)
Orphanet	ORPHA123920 (Hs)
Pharos	P08235 (Hs)
RefSeq Nucleotide	NM_000901 (Hs), NM_001083906 (Mm), NM_013131 (Rn)
RefSeq Protein	NP_000892 (Hs), NP_001159576 (Hs), NP_001077375 (Mm), NP_037263 (Rn)
SynPHARM	6580 (in complex with aldosterone) 6578 (in complex with deoxycorticosterone) 6583 (in complex with dexamethasone) 6579 (in complex with progesterone) 78981 (in complex with spironolactone)
UniProtKB	P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
Wikipedia	NR3C2 (Hs)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	DNA-binding Domain (Mineralocorticoid Receptor)
PDB Id:	4TNT
Resolution:	2.39Å
Species:	Human
References:	49

Description:	Mineralocorticoid receptor ligand binding domain with bound aldosterone.
PDB Id:	2AA2
Ligand:	aldosterone
Resolution:	1.95Å
Species:	Human
References:	9

Natural/Endogenous Ligands
aldosterone
corticosterone
cortisol
deoxycorticosterone
progesterone

Rank order of potency (Human)
corticosterone, cortisol, aldosterone, progesterone [95]

Rank order of potency (Human)

corticosterone, cortisol, aldosterone, progesterone [95]

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists

Key to terms and symbols

View all chemical structures

Click column headers to sort

Ligand		Sp.	Action	Value	Parameter	Reference
[³H]aldosterone		Rn	Agonist	9.4 – 9.5	pK_d	42,105
⤷	pK_d 9.4 – 9.5 (K_d 4x10^-10 – 3x10^-10 M) [42,105]
prednisolone		Hs	Agonist	7.4	pK_i	22
⤷	pK_i 7.4 (K_i 3.7x10^-8 M) [22]
budesonide		Hs	Agonist	7.8	pEC₅₀	47
⤷	pEC₅₀ 7.8 (EC₅₀ 1.4x10^-8 M) [47]
fluticasone propionate		Hs	Agonist	6.8	pEC₅₀	47
⤷	pEC₅₀ 6.8 (EC₅₀ 1.49x10^-7 M) [47]
deoxycorticosterone		Hs	Agonist	11.0	pIC₅₀	95
⤷	pIC₅₀ 11.0 [95]
fludrocortisone		Hs	Agonist	9.9	pIC₅₀	95
⤷	pIC₅₀ 9.9 [95]
aldosterone		Hs	Agonist	9.8 – 10.0	pIC₅₀	46,95
⤷	pIC₅₀ 9.8 – 10.0 [46,95]
cortisol		Hs	Agonist	9.8 – 9.9	pIC₅₀	46,95
⤷	pIC₅₀ 9.8 – 9.9 [46,95]
dexamethasone		Hs	Agonist	9.0	pIC₅₀	46,95
⤷	pIC₅₀ 9.0 [46,95]
prednisolone		Hs	Agonist	8.0	pIC₅₀	91
⤷	pIC₅₀ 8.0 (IC₅₀ 1.1x10^-8 M) [91]
AZD9567		Hs	Agonist	<4.4	pIC₅₀	91
⤷	pIC₅₀ <4.4 (IC₅₀ >3.8x10^-5 M) [91]
corticosterone		Hs	Agonist	-	-
⤷
benzodrocortisone		Hs	Agonist	-	-	31
⤷	[31]

View species-specific agonist tables

Antagonists

Key to terms and symbols

View all chemical structures

Click column headers to sort

Ligand		Sp.	Action	Value	Parameter	Reference
spironolactone		Hs	Antagonist	8.6	pK_i	4
⤷	pK_i 8.6 (K_i 2.32x10^-9 M) [4]
apararenone		Hs	Antagonist	7.0	pK_i	51
⤷	pK_i 7.0 (K_i 1x10^-7 M) [51] Description: Binding to hMR
eplerenone		Hs	Antagonist	6.9	pK_i	4
⤷	pK_i 6.9 (K_i 1.24x10^-7 M) [4]
AZD9977		Hs	Antagonist	<5.0	pK_i	43
⤷	pK_i <5.0 (K_i >1x10^-5 M) [43] Description: Binding affinity to hMR.
progesterone		Hs	Antagonist	11.0	pIC₅₀	95
⤷	pIC₅₀ 11.0 [95]
esaxerenone		Hs	Antagonist	8.6	pIC₅₀	53,81
⤷	pIC₅₀ 8.6 (IC₅₀ 2.4x10^-9 M) [53,81]
ocedurenone		Hs	Antagonist	8.6	pIC₅₀	21
⤷	pIC₅₀ 8.6 (IC₅₀ 2.7x10^-9 M) [21]
PF-03882845		Hs	Antagonist	8.0	pIC₅₀	20
⤷	pIC₅₀ 8.0 (IC₅₀ 9.2x10^-9 M) [20]
finerenone		Hs	Antagonist	7.7	pIC₅₀	17
⤷	pIC₅₀ 7.7 (IC₅₀ 1.8x10^-8 M) [17]
nimodipine		Hs	Antagonist	6.8	pIC₅₀	30
⤷	pIC₅₀ 6.8 (IC₅₀ 1.6x10^-7 M) inhibition of aldosterone-induced luciferase activity in a reporter system driven by the mineralocorticoid receptor ligand binding domain [30]
onapristone		Hs	Antagonist	6.3	pIC₅₀	126
⤷	pIC₅₀ 6.3 (IC₅₀ 4.7x10^-7 M) [126]
drospirenone		Hs	Antagonist	-	-	82
⤷	[82]
ZK112993		Hs	Antagonist	-	-
⤷
RU28318		Hs	Antagonist	-	-
⤷

Antagonist Comments

Several other antagonists are in various stages of development and are reviewed by Collin et al., 2014 [25].

DNA Binding

Structure:	Homodimer, Heterodimer
HRE core sequence:	ACAAGANNNTGTTCT
Response element:	GRE, Half site, Palindrome

DNA Binding Comments

MR and GR can heterodimerize. HRE sequence has variations that contribute to gene-specific regulation.

Additional response elements are described in Ziera et al., 2009 [128].

Analysis of the cistromes for the human and rat MRs is reported by Le Billan et al. (2015) [61] and van Weert et al. (2017) [114] respectively.

Co-binding Partners
Name	Interaction	Effect	Reference
Rac1			100
HMGD	Physical, Functional	DNA binding	11,116
Glucocorticoid receptor	Physical, Functional	DNA binding	63,66-68,75,111
HSP90 complex	Physical, Functional	Cellular localization	34,38-40,84
Epidermal growth factor receptor			44
Co-binding Partners Comments
MR interacts with other members of the HSP90 complex including, hsp70, p23, the FκBPs and the cyclopholins [16,85-86].

Main Co-regulators
Name	Activity	Specific	Ligand dependent	AF-2 dependent	Comments	References
PPARGC1A	Co-activator	No	Yes	No	Strong MR coactivator and highly expressed in brown adipocytes.	37
PPARGC1A	Co-activator	Yes	Yes	No	Elongation factor that directly interacts with the N-terminal domain of MR and acts as a potent coactivator; strongly represses GR transactivation and has no effect on AR or PR activity.	78
NCOA1	Co-activator	No	Yes	Yes	First member of a large coactivator family (SRC1, 2, 3). DNA-bound steroid receptors interact with SRC-1 which initiate sequential recruitment of SWI/SNF chromatin remodeling complexes, histone-methyltransferase proteins CARM1/PRMT1 and histone acetylases such as CBP/p300-pCAF. Sites of interaction with the MR: AF-2; AF-1 by SRC-1e isoform. Recruits histone acetylation complex to initiate transcription; weak intrinsic histone acetyltransferase activity.	50,76,118,125
NCOA2	Co-activator	-	No	Yes	Sites of interaction with the MR: AF-1, AF-2. Enhances transactivation.	37,48,118
EP300	Co-activator	-	No	Yes	Sites of interaction with the MR: AF-1, AF-2. Exerts histone acetyltransferase activity; recruits RNA polymerase II to target gene promoter.	37
PPARGC1A	Co-activator	-	No	Yes	Sites of interaction with the MR: AF-2. Recruits histone acetyltransferase complex; facilitates binding of NR to transcription initiation complex.	50,55
ELL	Co-activator	-	No	-	Sites of interaction with the MR: AF-1b. RNA polymerase II elongation factor; prevents premature arrest and transient pausing of polymerase II.	78
CASP8AP2	Co-activator	-	No	-	Sites of interaction with the MR: AF-1. Regulates cell apoptosis.	72
FAF1	Co-activator	-	No	-	Sites of interaction with the MR: AF-1. Regulates cell apoptosis.	72
NRIP1	Co-activator	-	No	-	Sites of interaction with the MR: N-terminal domain	125
NCOR2	Co-repressor	No	No	Yes	Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC). Sites of interaction with the MR: ligand binding domain.	118
NCOR1	Co-repressor	No	No	Yes	Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC). Sites of interaction with the MR: ligand binding domain.	118
NFYC	Co-repressor	-	No	-	Sites of interaction with the MR: AF-1. Inhibits aldosterone-induced MR N-C interaction.	65
PIAS1	Co-repressor	Yes	Yes	No	PIAS1, a SUMO-E3 ligase, inhibits transactivation by MR and AR but not that by GR. Sites of interaction with the MR: N-terminal domain, possibly ligand binding domain. Exact mechanism of repressive action unclear.	109
DAXX	Co-repressor	-	No	-	Sites of interaction with the MR: N-terminal domain. Regulates cell apoptosis; represses MR transactivation in some cell lines.	72
UBE2I	Co-activator	-	No	-	Sites of interaction with the MR: N-terminal domain. SUMO E2-conjugating enzyme; forms coactivation complex with SRC-1.	122
TRIM24	Co-activator	-	No	-	Sites of interaction with the MR: N-terminal domain. Transcriptional coactivator / corepressor.	125
RACK1	Co-activator	No	Yes	-	The mechanisms of the direct interaction has not been shown. The coactivation is dependent on phosphorylation of RACK1 by PKCβ.	59
GEMIN4	Co-repressor	Yes	Yes	Yes	Cell-specific repression of MR signalling.	120
TESMIN	Co-activator	Yes	Yes	Yes	Sites of interaction with the MR: AF-2. Aldosterone-specific.	93
Main Co-regulators Comments
A publication describing RHA as a MR co-regulator (Kitagawa et al., 2002) has been retracted [54,69]. XRCC6, EEF1A1 and SSRP1 are non-specific, ligand-dependent coregulators that confer tissue specific regulation [121].

Main Target Genes
Name	Species	Effect	Technique	Comments	References
Sgk1	Rat	Activated		the focal induction of serum and glucocorticoid-regulated kinase 1 (SGK1) is in the distal nephron and colon	7,14,101
Fxyd4	Rat	Activated		Fxyd4 or the chanel-inducing factor (Chif) is a member of the FXYD membrane protein family associated with Na+K+ATPase.	13
K-Ras2A	None	Activated	Northern blot analysis, real-time RT-PCR	Using the Xenopus laevis kidney-derived A6 cell line, the K-ras transcript of the K-ras gene was identified as aldosterone induced.	15,106
Mmp12	Mouse	Activated	PCR	Validated as apart of myeloid cell inflammatory response to MR activation.	74,99
Per1	Mouse	Activated	Microarray, Northern blot		45
Per2	Mouse	Activated	Microarray, Northern blot		45
Ctgf	Mouse	Activated	Microarray, Northern blot		45
Cnksr3/CNKSR3	Mouse	Activated	ChIP	NB: mouse AND human. Validated as part of the regulatory complex associated with ENaC	103,128
Fkbp5	Rat	Activated	qRT-PCR of endogenous target gene, Western blotting		80
WNK1	Human	Activated	Semiquantitative RT-PCR		70
ICAM1	Human	Activated	qRT-PCR, immunoblotting		19
Edn1	Rat	Activated	Northern blot analysis, real-time RT-PCR		119
Serpine1	Rat	Activated	RT-PCR		123
Ndrg2	Rat	Activated	RT-PCR		12
SCNN1A	Human	Activated		ENaC (SCNN1A) is transcriptionally regulated by aldosterone as an early event in distal colon but not in the kidney. However, aldosterone does increase ENaC number and activity on kidney epithelial cell surface.	1,102
GILZ/Tsc22d3	Mouse	Activated	Serial analysis of gene expression (SAGE)	Subsequently has been validated as a functionally relevant MR regulated gene in several tissues and species.	87,92,104
Main Target Genes Comments
K-Ras2 gene is activated by MR in Xenopus [115]. A small G protein and a proto-oncogene was found to be rapidly induced by aldosterone, enhances Na+ current. Other genes activated include the following: Na+, K+ ATPase α1 and β1 [56-57,57]. In addition to the genes listed above, regulation of L-type Ca2+ channel [62], osteogenic genes including alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP2) [52], the RNA polymerase II elongation factor ELL (eleven-nineteen lysine-rich leukemia; [78]), the ubiquitin-specific protease Usp2-45 [33], and Sgk1, Fkbp5, Rasl12, Tns1 and Tsc22d3 (Gilz) which were validated as direct target genes of MR by quantitative RT-qPCR and ChIP-qPCR in a study using a murine distal convoluted tubular epithelial cell-line [112].

Tissue Distribution

Brain, heart, kidney, colon, aorta, hippocampus, hypothalamus, adrenal fasciculata.

Species:	Human
Technique:	Northern, Q-PCR, in situ, Western, immunohistology
References:	27,58

Tissue Distribution Comments

Classic aldosterone-sensitive tissues include epithelia with high electrical resistance, such as the distal parts of the nephron, the surface epithelium of the distal colon, and salivary and sweat gland ducts. More recently, other MR-expressing cells have been identified, either epithelial, as in epidermal keratinocytes, or nonepithelial, as in the neurons of the central nervous system, the cardiac myocytes, and the endothelial and smooth muscle cells of the vasculature (large vessels). Similar patterns of expression are also seen in rodents.

There is also extensive documentation of MR expression in renal and cardiac cell types (reviewed in Odermatt and Kratschmar, 2012 [73]).

In addition to those human tissues listed above, there are now many more documented in the literature, including female reproductive tissues (ovary, breast), auditory and retinal tissues, inflammatory cells, particularly the monocyte/macrophage lineage, the rest of the gastrointestinal tract although highest levels are undoubtedly in the distal colon.

The MR is co-expressed with 11βHSD2 in a small number of nuclei in the nucleus of the solitary tract (NTS); in these nuclei the role of the MR is to regulate salt appetite in response to aldosterone and therefore sodium balance. They occupy a subregion of the NTS with a diminished blood brain barrier which may afford exposure to circulating aldosterone. These neurons express the angiotensin receptor and MR activation appears to interact synergistically with AngII to promote salt appetite [41,88].

Expression datasets are available from these referenes: [45,83,92,107].

Functional Assays

Renal clearance

Species:	Mouse
Tissue:	Urine
Response measured:	Ion levels
References:	5

Colonic transepithelial Na⁺ reabsorption

Species:	Mouse
Tissue:	Colon, in vivo
Response measured:	Colonic transepithelial potential difference is measured in vivo by a double-barreled flexible polyethylene tube that could be perfused by Ringer-type solution ± amiloride (3 µmol/liter). This tube was inserted into the rectum at a length of 7 mm. The electrical potential of this tube is measured by a high input resistance differential amplifier and was referenced to an Ag/AgCl electrode that was inserted under the skin
References:	5,102

Physiological Consequences of Altering Gene Expression

Homozygous MR-deficient mice:- show normal prenatal development, during week one they developed symptoms of pseudohypoaldosteronism, lost weight and died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations.

Species:	Mouse
Tissue:
Technique:	Gene targeting in embryonic stem cells
References:	5

A conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism.

Species:	Mouse
Tissue:	Heart
Technique:	Antisense oligonucleotide
References:	3

Gene targeting has been used to generate mice in which serine is substituted for cysteine at codon 603 in the MR; this mutation precludes DNA binding. These mice when bred to homozygosity show the same features as observed previously for mice null for the MR gene. This mouse model demonstrates that DNA binding is essential for the epithelial MR response.

Species:	Mouse
Tissue:
Technique:	Homologous recombination.
References:	23

Forebrain/CNS knockout: Impaired learning and memory, altered level of anxiety. Neural mossy-fibre abnormalities, increased GR levels in the brain.

Species:	Mouse
Tissue:	Neurons.
Technique:	CamKII-Cre
References:	6

Renal nephron knockout: Survive with severe PHA-1, die on Na⁺-deficient diet. Reduced renal ENaCα & Na⁺/Cl^- co-transporter levels.

Species:	Mouse
Tissue:	Nephron
Technique:	Pax8-Cre
References:	18,110

Renal tubule knockout: Survival to adult, elevated RAAS activity. Na⁺/water loss on a low sodium diet

Species:	Mouse
Tissue:	CD and CNT
Technique:	Aqp2-Cre
References:	94

Vascular smooth muscle cells (VSMC) knockout: impaired blood pressure regulation in ageing, altered vascular tone. Induced VSM α5-integrin, aldosterone/salt

Species:	Mouse
Tissue:	Smooth muscle
Technique:	SMA-CRE/ERT2
References:	64

Endothelial cell knockout: No ddeoxycorticosterone/salt-mediated cardiac fibrosis, no macrophage recruitment (Tie2-Cre). Obesity-induced dysfunction blunted inflammation (VE-Cad-Cre)

Species:	Mouse
Tissue:
Technique:	Tie2-Cre, VE-Cad-Cre
References:	90,98

Cardiomyocyte knockout: Improved cardiac remodelling post-infarct (MLC2a-Cre). Protected from deoxycorticosterone/salt-mediated cardiac fibrosis (MLC2v-Cre).

Species:	Mouse
Tissue:
Technique:	MLC2a-Cre, MLC2v-Cre
References:	35,71,89

Skin knockout: mice were resistant to age-induced epidermal atrophy but had reductions in dermal thickness, collagen deposition and SMAD2 and 3 activity.

Species:	Mouse
Tissue:	Epidermis
Technique:	K5-Cre
References:	8

Physiological Consequences of Altering Gene Expression Comments

There are now a series of tissue-specific MR knockouts. The physiology of these at baseline is limited although in a pathophysiology context the effects are profound (see [24]).

Phenotypes, Alleles and Disease Models

Mouse data from MGI

Show »« Hide

Allele	Composition & genetic background	Accession	Phenotype Id	Phenotype	Reference
Nr3c2^tm2Gsc\|Tg(Camk2a-cre)2Gsc	Nr3c2^tm2Gsc/Nr3c2^tm2Gsc,Tg(Camk2a-cre)2Gsc/0 involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:2181425 MGI:99459	MP:0002761	abnormal hippocampal mossy fiber morphology	PMID: 16368758
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0001765	abnormal ion homeostasis	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0002829	abnormal juxtaglomerular apparatus	PMID: 9689096
Nr3c2^tm1Krst\|Tg(Camk2a-cre)2Gsc	Nr3c2^tm1Krst/Nr3c2^tm1Krst,Tg(Camk2a-cre)2Gsc/? involves: FVB/N	MGI:2181425 MGI:99459	MP:0004753	abnormal miniature excitatory postsynaptic currents	PMID: 16361444
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0005325	abnormal renal glomerulus morphology	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0010109	abnormal renal sodium reabsorption	PMID: 9689096
Nr3c2^tm2Gsc\|Tg(Camk2a-cre)2Gsc	Nr3c2^tm2Gsc/Nr3c2^tm2Gsc,Tg(Camk2a-cre)2Gsc/0 involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:2181425 MGI:99459	MP:0003461	abnormal response to novel object	PMID: 16368758
Nr3c2^tm2Gsc\|Tg(Camk2a-cre)2Gsc	Nr3c2^tm2Gsc/Nr3c2^tm2Gsc,Tg(Camk2a-cre)2Gsc/0 involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:2181425 MGI:99459	MP:0001463	abnormal spatial learning	PMID: 16368758
Nr3c2^tm2Gsc\|Tg(Camk2a-cre)2Gsc	Nr3c2^tm2Gsc/Nr3c2^tm2Gsc,Tg(Camk2a-cre)2Gsc/0 involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:2181425 MGI:99459	MP:0008428	abnormal spatial working memory	PMID: 16368758
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0005634	decreased circulating sodium level	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0001429	dehydration	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0010128	hypovolemia	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0002666	increased circulating aldosterone level	PMID: 9689096
Nr3c2⁺\|Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2⁺ involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0002666	increased circulating aldosterone level	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0005627	increased circulating potassium level	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0003352	increased circulating renin level	PMID: 9689096
Nr3c2⁺\|Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2⁺ involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0003352	increased circulating renin level	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0002608	increased hematocrit	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0005582	increased renin activity	PMID: 9689096
Nr3c2⁺\|Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2⁺ involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0005582	increased renin activity	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0006316	increased urine sodium level	PMID: 9689096
Nr3c2⁺\|Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2⁺ involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0006316	increased urine sodium level	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0006275	natriuresis	PMID: 9689096
Nr3c2⁺\|Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2⁺ involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0006275	natriuresis	PMID: 9689096
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0002082	postnatal lethality	PMID: 9689096
Nr3c2^tm2.1Gsc	Nr3c2^tm2.1Gsc/Nr3c2^tm2.1Gsc involves: C57BL/6	MGI:99459	MP:0002082	postnatal lethality	PMID: 16368758
Nr3c2^tm1Gsc	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc involves: 129P2/OlaHsd * C57BL/6	MGI:99459	MP:0001263	weight loss	PMID: 9689096

Clinically-Relevant Mutations and Pathophysiology

Disease:

Pseudohyperaldosteronism type 2

Synonyms:	Hypertension, early-onset, autosomal dominant, with severe exacerbation in pregnancy [OMIM: 605115]
OMIM:	605115
Orphanet:	ORPHA88660

Comments:

Alteration at the receptor level: S819L mutant gains function.

References:

97,108

Click column headers to sort

Type	Species	Amino acid change	Nucleotide change	Description	Reference
Missense	Human	S819L		Gain of function

Disease:

Renal pseudohypoaldosteronism type 1

Synonyms:	Pseudohypoaldosteronism, type 1, autosomal dominant; PHA1A [OMIM: 177735]
OMIM:	177735
Orphanet:	ORPHA171871

Role:

A mild form of mineralocorticoid resistance involving only one allele. This is distinct from the severe autosomal recessive form of PHA1 which involves mutations in the epithelial sodium channel genes. Recent studies have addressed the broader consequences of haploinsufficiency that characterises PHA1 with MR mutations for the pituitary adrenal axis (Walker et al. 2014) and for the cardiovascular system (Escoubet et al., 2013).

Comments:

Alteration at the receptor level: G633R, Q776R, L924P and L979P mutants lose activity.

References:

32,97,108,117,124

Click column headers to sort

Type	Species	Amino acid change	Description	Reference
Missense	Human	G633R	Loss of function	97
Missense	Human	Q776R	Loss of function	97
Missense	Human	L924P	Loss of function	108
Missense	Human	L979P	Loss of function	97

Biologically Significant Variants

Type:	Polymorphism
Species:	Human
Description:	A G/C polymorphism at position -2 of the human MR mRNA 5’-untranslated region has been associated with activation of the RAAS and regulation of blood pressure. The G allele was associated with both lower MR levels and together with lower transcriptional activity, and whereas the GG genotype correlated with higher plasma aldosterone levels and higher blood pressure in males. G allele carriers exhibit a greater cortisol response to stress and altered performance strategies in learning tests [2].
Nucleotide change:	.-2G>C
Global MAF (%):	0.45
References:	60,113

Type:	Polymorphism
Species:	Human
Description:	A 538A>G mutation in exon 2 causes an Ile180Val missense change in the N-terminal domain of the human MR.In healthy human subjects, responses to psychosocial stress showed cortisol levels and heart rate were enhanced for the G/Val allele
Amino acid change:	Ile180Val
Nucleotide change:	538A>G
References:	29

Type:	Truncation
Species:	Human
Description:	A Gln919STOP, maternally inherited mutation in the human MR ligand-binding domain has been identified in three brothers with autism. Gln919 lies in helix 10, and although Gln 919 does not lie in the ligand-binding pocket, the truncation alters portions of the pocket and of AF-2. How this mutation affects MR signalling is unknown. Other human MR variants have been reported to be associated with autism, a condition which is characterised by altered levels of stress and responses to anxiety
Amino acid change:	Gln919STOP
References:	26,28,96

Type:	Species variant
Species:	Human
Description:	Threonine at position 870 in helix 8 of the LBD in the human MR is conserved across terrestrial vertebrates (except in rodents where there is a serine at the equivalent position). In contrast a leucine occurs at the equivalent position in the fish MR enabling it to form a stabilizing bond with a leucine in helix 1 of the LBD. This evolutionary switch, leucine to threonine/serine is responsible for progesterone (and spironolactone) being an agonist in fish and an antagonist in terrestrial vertebrates.
Amino acid change:	Leu870>Thr/Ser
References:	36

Type:	Alternative promoters and splicing
Species:	Human
Description:	mineralocorticoid receptor isoform 1 (MR-A) is the full length transcript
Protein accession:	NP_000892
References:	77

Type:	Alternative promoters and splicing
Species:	Human
Description:	mineralocorticoid receptor isoform 2 (MR-B) is an N-terminus truncated transcript of hMR
Protein accession:	NP_001159576
References:	77

Biologically Significant Variant Comments

Human mineralocorticoid receptor isoform 1 (MR-A) has higher transactivation activity than MR-B. Other splicing variants include: A 12-bp insertion at the 3' of exon 3 results in a four-residue addition in between the two zinc fingers of the DBD and no difference in activity compared to the wild-type receptor; a 10-bp deletion in rat MR results truncated LBD at residue 807, unresponsive to aldosterone, and no interference with wild-tpe receptor function; exon-skipping in human generates mutants lacking exon 5 or both exons 5 and 6 which binds to DNA and modulate wild-type receptor activity in a ligand-independent manner [10,125,127].

References

Show »« Hide

1. Amasheh S, Epple HJ, Mankertz J, Detjen K, Goltz M, Schulzke JD, Fromm M. (2000) Differential regulation of ENaC by aldosterone in rat early and late distal colon. Ann N Y Acad Sci, 915: 92-4. [PMID:11193605]

2. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. (1987) Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science, 237 (4812): 268-75. [PMID:3037703]

3. Beggah AT, Escoubet B, Puttini S, Cailmail S, Delage V, Ouvrard-Pascaud A, Bocchi B, Peuchmaur M, Delcayre C, Farman N, Jaisser F. (2002) Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes. Proc Natl Acad Sci USA, 99 (10): 7160-5. [PMID:11997477]

4. Bell MG, Gernert DL, Grese TA, Belvo MD, Borromeo PS, Kelley SA, Kennedy JH, Kolis SP, Lander PA, Richey R et al.. (2007) (S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor. J Med Chem, 50 (26): 6443-5. [PMID:18038968]

5. Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Kriz W, Warth R, Greger R, Schütz G. (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci USA, 95 (16): 9424-9. [PMID:9689096]

6. Berger S, Wolfer DP, Selbach O, Alter H, Erdmann G, Reichardt HM, Chepkova AN, Welzl H, Haas HL, Lipp HP et al.. (2006) Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity. Proc Natl Acad Sci U S A, 103 (1): 195-200. [PMID:16368758]

7. Bhargava A, Fullerton MJ, Myles K, Purdy TM, Funder JW, Pearce D, Cole TJ. (2001) The serum- and glucocorticoid-induced kinase is a physiological mediator of aldosterone action. Endocrinology, 142 (4): 1587-94. [PMID:11250940]

8. Bigas J, Sevilla LM, Pérez P. (2020) Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice. J Invest Dermatol, 140 (10): 1899-1908. [PMID:32199993]

9. Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, Stanley TB, Stewart EL, Trump RP, Willson TM, Williams SP. (2005) A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor. J Biol Chem, 280 (35): 31283-93. [PMID:15967794]

10. Bloem LJ, Guo C, Pratt JH. (1995) Identification of a splice variant of the rat and human mineralocorticoid receptor genes. J Steroid Biochem Mol Biol, 55 (2): 159-62. [PMID:7495694]

11. Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, Nordeen SK, Allegretto EA, Edwards DP. (1998) High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol Cell Biol, 18 (8): 4471-87. [PMID:9671457]

12. Boulkroun S, Fay M, Zennaro MC, Escoubet B, Jaisser F, Blot-Chabaud M, Farman N, Courtois-Coutry N. (2002) Characterization of rat NDRG2 (N-Myc downstream regulated gene 2), a novel early mineralocorticoid-specific induced gene. J Biol Chem, 277 (35): 31506-15. [PMID:12072429]

13. Brennan FE, Fuller PJ. (1999) Acute regulation by corticosteroids of channel-inducing factor gene messenger ribonucleic acid in the distal colon. Endocrinology, 140 (3): 1213-8. [PMID:10067846]

14. Brennan FE, Fuller PJ. (2000) Rapid upregulation of serum and glucocorticoid-regulated kinase (sgk) gene expression by corticosteroids in vivo. Mol Cell Endocrinol, 166 (2): 129-36. [PMID:10996431]

15. Brennan FE, Fuller PJ. (2006) Mammalian K-ras2 is a corticosteroid-induced gene in vivo. Endocrinology, 147 (6): 2809-16. [PMID:16543373]

16. Bruner KL, Derfoul A, Robertson NM, Guerriero G, Fernandes-Alnemri T, Alnemri ES, Litwack G. (1997) The unliganded mineralocorticoid receptor is associated with heat shock proteins 70 and 90 and the immunophilin FKBP-52. Recept Signal Transduct, 7 (2): 85-98. [PMID:9392437]

17. Bärfacker L, Kuhl A, Hillisch A, Grosser R, Figueroa-Pérez S, Heckroth H, Nitsche A, Ergüden JK, Gielen-Haertwig H, Schlemmer KH et al.. (2012) Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem, 7 (8): 1385-403. [PMID:22791416]

18. Canonica J, Sergi C, Maillard M, Klusonova P, Odermatt A, Koesters R, Loffing-Cueni D, Loffing J, Rossier B, Frateschi S et al.. (2016) Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype. Pflugers Arch, 468 (5): 895-908. [PMID:26762397]

19. Caprio M, Newfell BG, la Sala A, Baur W, Fabbri A, Rosano G, Mendelsohn ME, Jaffe IZ. (2008) Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion. Circ Res, 102 (11): 1359-67. [PMID:18467630]

20. Casimiro-Garcia A, Piotrowski DW, Ambler C, Arhancet GB, Banker ME, Banks T, Boustany-Kari CM, Cai C, Chen X, Eudy R et al.. (2014) Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist. J Med Chem, 57 (10): 4273-88. [PMID:24738581]

21. Chow CP, Liu JR, Tan XJ, Huang ZH. (2017) Pharmacological Profile of KBP-5074, a Novel NonSteroidal Mineralocorticoid Receptor Antagonist for the Treatment of Cardiorenal Diseases. ournal of Drug Research and Development, 3 (2). DOI: 10.16966/2470-1009.137

22. Coghlan MJ, Kym PR, Elmore SW, Wang AX, Luly JR, Wilcox D, Stashko M, Lin CW, Miner J, Tyree C et al.. (2001) Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: selective quinoline derivatives with prednisolone-equivalent functional activity. J Med Chem, 44 (18): 2879-85. [PMID:11520196]

23. Cole TJ, Terella L, Morgan J, Alexiadis M, Yao YZ, Enriori P, Young MJ, Fuller PJ. (2015) Aldosterone-Mediated Renal Sodium Transport Requires Intact Mineralocorticoid Receptor DNA-Binding in the Mouse. Endocrinology, 156 (8): 2958-68. [PMID:26066075]

24. Cole TJ, Young MJ. (2017) 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles. J Endocrinol, 234 (1): T83-T92. [PMID:28550025]

25. Collin M, Niemann F, Jaisser F. (2014) Mineralocorticoid receptor modulators: a patent review (2007 - 2012). Expert Opin Ther Pat, 24 (2): 177-83. [PMID:24215301]

26. Cukier HN, Griswold AJ, Hofmann NK, Gomez L, Whitehead PL, Abramson RK, Gilbert JR, Cuccaro ML, Dykxhoorn DM, Pericak-Vance MA. (2020) Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2. Autism Res, 13 (4): 523-531. [PMID:32064789]

27. de Kloet ER, Van Acker SA, Sibug RM, Oitzl MS, Meijer OC, Rahmouni K, de Jong W. (2000) Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int, 57 (4): 1329-36. [PMID:10760063]

28. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S et al.. (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515 (7526): 209-15. [PMID:25363760]

29. DeRijk RH, Wüst S, Meijer OC, Zennaro MC, Federenko IS, Hellhammer DH, Giacchetti G, Vreugdenhil E, Zitman FG, de Kloet ER. (2006) A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab, 91 (12): 5083-9. [PMID:17018659]

30. Dietz JD, Du S, Bolten CW, Payne MA, Xia C, Blinn JR, Funder JW, Hu X. (2008) A number of marketed dihydropyridine calcium channel blockers have mineralocorticoid receptor antagonist activity. Hypertension, 51 (3): 742-8. [PMID:18250364]

31. Edelman JL, Nehme A. (2013) PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE OF 4-PREGENEN-11ß-17-21-TRIOL-3,20-DIONE DERIVATIVES. Patent number: WO2013071010. Assignee: Allergan, Inc.. Priority date: 11/11/2011. Publication date: 16/05/2013.

32. Escoubet B, Couffignal C, Laisy JP, Mangin L, Chillon S, Laouénan C, Serfaty JM, Jeunemaitre X, Mentré F, Zennaro MC. (2013) Cardiovascular effects of aldosterone: insight from adult carriers of mineralocorticoid receptor mutations. Circ Cardiovasc Genet, 6 (4): 381-90. [PMID:23852419]

33. Fakitsas P, Adam G, Daidié D, van Bemmelen MX, Fouladkou F, Patrignani A, Wagner U, Warth R, Camargo SM, Staub O et al.. (2007) Early aldosterone-induced gene product regulates the epithelial sodium channel by deubiquitylation. J Am Soc Nephrol, 18 (4): 1084-92. [PMID:17344426]

34. Faresse N, Ruffieux-Daidie D, Salamin M, Gomez-Sanchez CE, Staub O. (2010) Mineralocorticoid receptor degradation is promoted by Hsp90 inhibition and the ubiquitin-protein ligase CHIP. Am J Physiol Renal Physiol, 299 (6): F1462-72. [PMID:20861078]

35. Fraccarollo D, Berger S, Galuppo P, Kneitz S, Hein L, Schütz G, Frantz S, Ertl G, Bauersachs J. (2011) Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation, 123 (4): 400-8. [PMID:21242479]

36. Fuller PJ, Yao YZ, Jin R, He S, Martín-Fernández B, Young MJ, Smith BJ. (2019) Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist. Proc Natl Acad Sci U S A, 116 (37): 18578-18583. [PMID:31439819]

37. Fuse H, Kitagawa H, Kato S. (2000) Characterization of transactivational property and coactivator mediation of rat mineralocorticoid receptor activation function-1 (AF-1). Mol Endocrinol, 14 (6): 889-99. [PMID:10847590]

38. Galigniana MD, Echeverría PC, Erlejman AG, Piwien-Pilipuk G. (2010) Role of molecular chaperones and TPR-domain proteins in the cytoplasmic transport of steroid receptors and their passage through the nuclear pore. Nucleus, 1 (4): 299-308. [PMID:21113270]

39. Galigniana MD, Erlejman AG, Monte M, Gomez-Sanchez C, Piwien-Pilipuk G. (2010) The hsp90-FKBP52 complex links the mineralocorticoid receptor to motor proteins and persists bound to the receptor in early nuclear events. Mol Cell Biol, 30 (5): 1285-98. [PMID:20038533]

40. Gallo LI, Ghini AA, Piwien Pilipuk G, Galigniana MD. (2007) Differential recruitment of tetratricorpeptide repeat domain immunophilins to the mineralocorticoid receptor influences both heat-shock protein 90-dependent retrotransport and hormone-dependent transcriptional activity. Biochemistry, 46 (49): 14044-57. [PMID:18001136]

41. Gasparini S, Resch JM, Narayan SV, Peltekian L, Iverson GN, Karthik S, Geerling JC. (2019) Aldosterone-sensitive HSD2 neurons in mice. Brain Struct Funct, 224 (1): 387-417. [PMID:30343334]

42. Ge RS, Dong Q, Sottas CM, Latif SA, Morris DJ, Hardy MP. (2005) Stimulation of testosterone production in rat Leydig cells by aldosterone is mineralocorticoid receptor mediated. Mol Cell Endocrinol, 243 (1-2): 35-42. [PMID:16188378]

43. Granberg KL, Yuan ZQ, Lindmark B, Edman K, Kajanus J, Hogner A, Malmgren M, O'Mahony G, Nordqvist A, Lindberg J et al.. (2019) Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection. J Med Chem, 62 (3): 1385-1406. [PMID:30596500]

44. Grossmann C, Gekle M. (2012) Interaction between mineralocorticoid receptor and epidermal growth factor receptor signaling. Mol Cell Endocrinol, 350 (2): 235-41. [PMID:21827828]

45. Gumz ML, Popp MP, Wingo CS, Cain BD. (2003) Early transcriptional effects of aldosterone in a mouse inner medullary collecting duct cell line. Am J Physiol Renal Physiol, 285 (4): F664-73. [PMID:12770840]

46. Hellal-Levy C, Couette B, Fagart J, Souque A, Gomez-Sanchez C, Rafestin-Oblin M. (1999) Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett, 464 (1-2): 9-13. [PMID:10611474]

47. Hemmerling M, Nilsson S, Edman K, Eirefelt S, Russell W, Hendrickx R, Johnsson E, Kärrman Mårdh C, Berger M, Rehwinkel H et al.. (2017) Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases. J Med Chem, 60 (20): 8591-8605. [PMID:28937774]

48. Hong H, Kohli K, Garabedian MJ, Stallcup MR. (1997) GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol, 17 (5): 2735-44. [PMID:9111344]

49. Hudson WH, Youn C, Ortlund EA. (2014) Crystal structure of the mineralocorticoid receptor DNA binding domain in complex with DNA. PLoS ONE, 9 (9): e107000. [PMID:25188500]

50. Hultman ML, Krasnoperova NV, Li S, Du S, Xia C, Dietz JD, Lala DS, Welsch DJ, Hu X. (2005) The ligand-dependent interaction of mineralocorticoid receptor with coactivator and corepressor peptides suggests multiple activation mechanisms. Mol Endocrinol, 19 (6): 1460-73. [PMID:15761029]

51. Iijima T, Katoh M, Takedomi K, Yamamoto Y, Akatsuka H, Shirata N, Nishi A, Takakuwa M, Watanabe Y, Munakata H et al.. (2022) Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist. J Med Chem, 65 (12): 8127-8143. [PMID:35652647]

52. Jaffe IZ, Tintut Y, Newfell BG, Demer LL, Mendelsohn ME. (2007) Mineralocorticoid receptor activation promotes vascular cell calcification. Arterioscler Thromb Vasc Biol, 27 (4): 799-805. [PMID:17234727]

53. Kato M, Furuie H, Shimizu T, Miyazaki A, Kobayashi F, Ishizuka H. (2018) Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects. Br J Clin Pharmacol, 84 (8): 1821-1829. [PMID:29688582]

54. Kitagawa H, Yanagisawa J, Fuse H, Ogawa S, Yogiashi Y, Okuno A, Nagasawa H, Nakajima T, Matsumoto T, Kato S. (2002) Ligand-selective potentiation of rat mineralocorticoid receptor activation function 1 by a CBP-containing histone acetyltransferase complex. Mol Cell Biol, 22 (11): 3698-706. [PMID:11997506]

55. Knutti D, Kaul A, Kralli A. (2000) A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen. Mol Cell Biol, 20 (7): 2411-22. [PMID:10713165]

56. Kolla V, Litwack G. (2000) Transcriptional regulation of the human Na/K ATPase via the human mineralocorticoid receptor. Mol Cell Biochem, 204 (1-2): 35-40. [PMID:10718622]

57. Kolla V, Robertson NM, Litwack G. (1999) Identification of a mineralocorticoid/glucocorticoid response element in the human Na/K ATPase alpha1 gene promoter. Biochem Biophys Res Commun, 266 (1): 5-14. [PMID:10581156]

58. Krozowski ZS, Funder JW. (1983) Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci USA, 80 (19): 6056-60. [PMID:6310613]

59. Kuppusamy M, Gomez-Sanchez EP, Beloate LN, Plonczynski M, Naray-Fejes-Toth A, Fejes-Toth G, Gomez-Sanchez CE. (2017) Interaction of the Mineralocorticoid Receptor With RACK1 and Its Role in Aldosterone Signaling. Endocrinology, 158 (7): 2367-2375. [PMID:28472300]

60. Langer K, Moser D, Otto T, Wolf OT, Kumsta R. (2019) Cortisol modulates the engagement of multiple memory systems: Exploration of a common NR3C2 polymorphism. Psychoneuroendocrinology, 107: 133-140. [PMID:31128569]

61. Le Billan F, Khan JA, Lamribet K, Viengchareun S, Bouligand J, Fagart J, Lombès M. (2015) Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells. FASEB J, 29 (9): 3977-89. [PMID:26054365]

62. Lesouhaitier O, Chiappe A, Rossier MF. (2001) Aldosterone increases T-type calcium currents in human adrenocarcinoma (H295R) cells by inducing channel expression. Endocrinology, 142 (10): 4320-30. [PMID:11564691]

63. Liu W, Wang J, Sauter NK, Pearce D. (1995) Steroid receptor heterodimerization demonstrated in vitro and in vivo. Proc Natl Acad Sci USA, 92 (26): 12480-4. [PMID:8618925]

64. McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, Chambon P, Hill MA, Dorrance AM, Mendelsohn ME et al.. (2012) Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med, 18 (9): 1429-33. [PMID:22922412]

65. Murai-Takeda A, Shibata H, Kurihara I, Kobayashi S, Yokota K, Suda N, Mitsuishi Y, Jo R, Kitagawa H, Kato S et al.. (2010) NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor. J Biol Chem, 285 (11): 8084-93. [PMID:20054001]

66. Nishi M. (2010) Imaging of transcription factor trafficking in living cells: lessons from corticosteroid receptor dynamics. Methods Mol Biol, 647: 199-212. [PMID:20694669]

67. Nishi M, Kawata M. (2007) Dynamics of glucocorticoid receptor and mineralocorticoid receptor: implications from live cell imaging studies. Neuroendocrinology, 85 (3): 186-92. [PMID:17446698]

68. Nishi M, Tanaka M, Matsuda K, Sunaguchi M, Kawata M. (2004) Visualization of glucocorticoid receptor and mineralocorticoid receptor interactions in living cells with GFP-based fluorescence resonance energy transfer. J Neurosci, 24 (21): 4918-27. [PMID:15163683]

69. No authors listed. (2014) Retraction for Kitagawa et al., Ligand-selective potentiation of rat mineralocorticoid receptor activation function 1 by a CBP-containing histone acetyltransferase complex. Mol Cell Biol, 34 (5): 916. [PMID:24509261]

70. Náray-Fejes-Tóth A, Snyder PM, Fejes-Tóth G. (2004) The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport. Proc Natl Acad Sci USA, 101 (50): 17434-9. [PMID:15583131]

71. Oakley RH, Cruz-Topete D, He B, Foley JF, Myers PH, Xu X, Gomez-Sanchez CE, Chambon P, Willis MS, Cidlowski JA. (2019) Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice. Sci Signal, 12 (577). [PMID:30992401]

72. Obradović D, Tirard M, Némethy Z, Hirsch O, Gronemeyer H, Almeida OF. (2004) DAXX, FLASH, and FAF-1 modulate mineralocorticoid and glucocorticoid receptor-mediated transcription in hippocampal cells--toward a basis for the opposite actions elicited by two nuclear receptors?. Mol Pharmacol, 65 (3): 761-9. [PMID:14978255]

73. Odermatt A, Kratschmar DV. (2012) Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases: an overview. Mol Cell Endocrinol, 350 (2): 168-86. [PMID:21820034]

74. Ong GSY, Cole TJ, Tesch GH, Morgan J, Dowling JK, Mansell A, Fuller PJ, Young MJ. (2020) Novel mineralocorticoid receptor mechanisms regulate cardiac tissue inflammation in male mice. J Endocrinol, 246 (2): 123-134. [PMID:32464598]

75. Ou XM, Storring JM, Kushwaha N, Albert PR. (2001) Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene. J Biol Chem, 276 (17): 14299-307. [PMID:11278286]

76. Oñate SA, Tsai SY, Tsai MJ, O'Malley BW. (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science, 270 (5240): 1354-7. [PMID:7481822]

77. Pascual-Le Tallec L, Demange C, Lombès M. (2004) Human mineralocorticoid receptor A and B protein forms produced by alternative translation sites display different transcriptional activities. Eur J Endocrinol, 150 (4): 585-90. [PMID:15080790]

78. Pascual-Le Tallec L, Simone F, Viengchareun S, Meduri G, Thirman MJ, Lombès M. (2005) The elongation factor ELL (eleven-nineteen lysine-rich leukemia) is a selective coregulator for steroid receptor functions. Mol Endocrinol, 19 (5): 1158-69. [PMID:15650021]

79. Patel PD, Sherman TG, Goldman DJ, Watson SJ. (1989) Molecular cloning of a mineralocorticoid (type I) receptor complementary DNA from rat hippocampus. Mol Endocrinol, 3 (11): 1877-85. [PMID:2558305]

80. Petrovich E, Asher C, Garty H. (2014) Induction of FKBP51 by aldosterone in intestinal epithelium. J Steroid Biochem Mol Biol, 139: 78-87. [PMID:24139875]

81. Piotrowski DW. (2012) Mineralocorticoid receptor antagonists for the treatment of hypertension and diabetic nephropathy. J Med Chem, 55 (18): 7957-66. [PMID:22866979]

82. Pollow K, Juchem M, Elger W, Jacobi N, Hoffmann G, Möbus V. (1992) Dihydrospirorenone (ZK30595): a novel synthetic progestagen--characterization of binding to different receptor proteins. Contraception, 46 (6): 561-74. [PMID:1493716]

83. Poulsen SB, Limbutara K, Fenton RA, Pisitkun T, Christensen BM. (2018) RNA sequencing of kidney distal tubule cells reveals multiple mediators of chronic aldosterone action. Physiol Genomics, 50 (5): 343-354. [PMID:29521601]

84. Pratt WB, Galigniana MD, Morishima Y, Murphy PJ. (2004) Role of molecular chaperones in steroid receptor action. Essays Biochem, 40: 41-58. [PMID:15242338]

85. Pratt WB, Toft DO. (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev, 18 (3): 306-60. [PMID:9183567]

86. Rafestin-Oblin ME, Couette B, Radanyi C, Lombes M, Baulieu EE. (1989) Mineralocorticosteroid receptor of the chick intestine. Oligomeric structure and transformation. J Biol Chem, 264 (16): 9304-9. [PMID:2542305]

87. Rashmi P, Colussi G, Ng M, Wu X, Kidwai A, Pearce D. (2017) Glucocorticoid-induced leucine zipper protein regulates sodium and potassium balance in the distal nephron. Kidney Int, 91 (5): 1159-1177. [PMID:28094030]

88. Resch JM, Fenselau H, Madara JC, Wu C, Campbell JN, Lyubetskaya A, Dawes BA, Tsai LT, Li MM, Livneh Y et al.. (2017) Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling. Neuron, 96 (1): 190-206.e7. [PMID:28957668]

89. Rickard AJ, Morgan J, Bienvenu LA, Fletcher EK, Cranston GA, Shen JZ, Reichelt ME, Delbridge LM, Young MJ. (2012) Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis. Hypertension, 60 (6): 1443-50. [PMID:23108646]

90. Rickard AJ, Morgan J, Chrissobolis S, Miller AA, Sobey CG, Young MJ. (2014) Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure. Hypertension, 63 (5): 1033-40. [PMID:24566081]

91. Ripa L, Edman K, Dearman M, Edenro G, Hendrickx R, Ullah V, Chang HF, Lepistö M, Chapman D, Geschwindner S et al.. (2018) Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile. J Med Chem, 61 (5): 1785-1799. [PMID:29424542]

92. Robert-Nicoud M, Flahaut M, Elalouf JM, Nicod M, Salinas M, Bens M, Doucet A, Wincker P, Artiguenave F, Horisberger JD et al.. (2001) Transcriptome of a mouse kidney cortical collecting duct cell line: effects of aldosterone and vasopressin. Proc Natl Acad Sci U S A, 98 (5): 2712-6. [PMID:11226305]

93. Rogerson FM, Yao YZ, Young MJ, Fuller PJ. (2014) Identification and characterization of a ligand-selective mineralocorticoid receptor coactivator. FASEB J, 28 (10): 4200-10. [PMID:24907116]

94. Ronzaud C, Loffing J, Bleich M, Gretz N, Gröne HJ, Schütz G, Berger S. (2007) Impairment of sodium balance in mice deficient in renal principal cell mineralocorticoid receptor. J Am Soc Nephrol, 18 (6): 1679-87. [PMID:17475815]

95. Rupprecht R, Reul JM, van Steensel B, Spengler D, Söder M, Berning B, Holsboer F, Damm K. (1993) Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur J Pharmacol, 247 (2): 145-54. [PMID:8282004]

96. Ruzzo EK, Pérez-Cano L, Jung JY, Wang LK, Kashef-Haghighi D, Hartl C, Singh C, Xu J, Hoekstra JN, Leventhal O et al.. (2019) Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Cell, 178 (4): 850-866.e26. [PMID:31398340]

97. Sartorato P, Cluzeaud F, Fagart J, Viengchareun S, Lombès M, Zennaro MC. (2004) New naturally occurring missense mutations of the human mineralocorticoid receptor disclose important residues involved in dynamic interactions with deoxyribonucleic acid, intracellular trafficking, and ligand binding. Mol Endocrinol, 18 (9): 2151-65. [PMID:15192075]

98. Schäfer N, Lohmann C, Winnik S, van Tits LJ, Miranda MX, Vergopoulos A, Ruschitzka F, Nussberger J, Berger S, Lüscher TF et al.. (2013) Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity. Eur Heart J, 34 (45): 3515-24. [PMID:23594590]

99. Shen JZ, Morgan J, Tesch GH, Rickard AJ, Chrissobolis S, Drummond GR, Fuller PJ, Young MJ. (2016) Cardiac Tissue Injury and Remodeling Is Dependent Upon MR Regulation of Activation Pathways in Cardiac Tissue Macrophages. Endocrinology, 157 (8): 3213-23. [PMID:27253999]

100. Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, Miyoshi J, Takai Y, Fujita T. (2008) Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med, 14 (12): 1370-6. [PMID:19029984]

101. Shigaev A, Asher C, Latter H, Garty H, Reuveny E. (2000) Regulation of sgk by aldosterone and its effects on the epithelial Na(+) channel. Am J Physiol Renal Physiol, 278 (4): F613-9. [PMID:10751222]

102. Skrabal F, Auböck J, Edwards CR, Braunsteiner H. (1978) Subtraction potential difference: In-vivo assay for mineralocorticoid activity. Lancet, 1 (8059): 298-302. [PMID:75336]

103. Soundararajan R, Pearce D, Ziera T. (2012) The role of the ENaC-regulatory complex in aldosterone-mediated sodium transport. Mol Cell Endocrinol, 350 (2): 242-7. [PMID:22101317]

104. Soundararajan R, Zhang TT, Wang J, Vandewalle A, Pearce D. (2005) A novel role for glucocorticoid-induced leucine zipper protein in epithelial sodium channel-mediated sodium transport. J Biol Chem, 280 (48): 39970-81. [PMID:16216878]

105. Stephenson G, Krozowski Z, Funder JW. (1984) Extravascular CBG-like sites in rat kidney and mineralocorticoid receptor specificity. Am J Physiol, 246 (2 Pt 2): F227-33. [PMID:6320679]

106. Stockand JD, Spier BJ, Worrell RT, Yue G, Al-Baldawi N, Eaton DC. (1999) Regulation of Na(+) reabsorption by the aldosterone-induced small G protein K-Ras2A. J Biol Chem, 274 (50): 35449-54. [PMID:10585415]

107. Swanson EA, Nelson JW, Jeng S, Erspamer KJ, Yang CL, McWeeney S, Ellison DH. (2019) Salt-sensitive transcriptome of isolated kidney distal tubule cells. Physiol Genomics, 51 (4): 125-135. [PMID:30875275]

108. Tajima T, Kitagawa H, Yokoya S, Tachibana K, Adachi M, Nakae J, Suwa S, Katoh S, Fujieda K. (2000) A novel missense mutation of mineralocorticoid receptor gene in one Japanese family with a renal form of pseudohypoaldosteronism type 1. J Clin Endocrinol Metab, 85 (12): 4690-4. [PMID:11134129]

109. Tallec LP, Kirsh O, Lecomte MC, Viengchareun S, Zennaro MC, Dejean A, Lombès M. (2003) Protein inhibitor of activated signal transducer and activator of transcription 1 interacts with the N-terminal domain of mineralocorticoid receptor and represses its transcriptional activity: implication of small ubiquitin-related modifier 1 modification. Mol Endocrinol, 17 (12): 2529-42. [PMID:14500761]

110. Terker AS, Yarbrough B, Ferdaus MZ, Lazelle RA, Erspamer KJ, Meermeier NP, Park HJ, McCormick JA, Yang CL, Ellison DH. (2016) Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport. J Am Soc Nephrol, 27 (8): 2436-45. [PMID:26712527]

111. Trapp T, Rupprecht R, Castrén M, Reul JM, Holsboer F. (1994) Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS. Neuron, 13 (6): 1457-62. [PMID:7993637]

112. Ueda K, Fujiki K, Shirahige K, Gomez-Sanchez CE, Fujita T, Nangaku M, Nagase M. (2014) Genome-wide analysis of murine renal distal convoluted tubular cells for the target genes of mineralocorticoid receptor. Biochem Biophys Res Commun, 445 (1): 132-7. [PMID:24491541]

113. van Leeuwen N, Caprio M, Blaya C, Fumeron F, Sartorato P, Ronconi V, Giacchetti G, Mantero F, Fernandes-Rosa FL, Simian C et al.. (2010) The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels. Hypertension, 56 (5): 995-1002. [PMID:20855654]

114. van Weert LTCM, Buurstede JC, Mahfouz A, Braakhuis PSM, Polman JAE, Sips HCM, Roozendaal B, Balog J, de Kloet ER, Datson NA et al.. (2017) NeuroD Factors Discriminate Mineralocorticoid From Glucocorticoid Receptor DNA Binding in the Male Rat Brain. Endocrinology, 158 (5): 1511-1522. [PMID:28324065]

115. Verrey F. (1999) Early aldosterone action: toward filling the gap between transcription and transport. Am J Physiol, 277 (3 Pt 2): F319-27. [PMID:10484514]

116. Verrijdt G, Haelens A, Schoenmakers E, Rombauts W, Claessens F. (2002) Comparative analysis of the influence of the high-mobility group box 1 protein on DNA binding and transcriptional activation by the androgen, glucocorticoid, progesterone and mineralocorticoid receptors. Biochem J, 361 (Pt 1): 97-103. [PMID:11742533]

117. Walker BR, Andrew R, Escoubet B, Zennaro MC. (2014) Activation of the hypothalamic-pituitary-adrenal axis in adults with mineralocorticoid receptor haploinsufficiency. J Clin Endocrinol Metab, 99 (8): E1586-91. [PMID:24712576]

118. Wang Q, Anzick S, Richter WF, Meltzer P, Simons SS. (2004) Modulation of transcriptional sensitivity of mineralocorticoid and estrogen receptors. J Steroid Biochem Mol Biol, 91 (4-5): 197-210. [PMID:15336697]

119. Wong S, Brennan FE, Young MJ, Fuller PJ, Cole TJ. (2007) A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology, 148 (4): 1511-7. [PMID:17218419]

120. Yang J, Fuller PJ, Morgan J, Shibata H, Clyne CD, Young MJ. (2015) GEMIN4 functions as a coregulator of the mineralocorticoid receptor. J Mol Endocrinol, 54 (2): 149-60. [PMID:25555524]

121. Yang J, Fuller PJ, Morgan J, Shibata H, McDonnell DP, Clyne CD, Young MJ. (2014) Use of phage display to identify novel mineralocorticoid receptor-interacting proteins. Mol Endocrinol, 28 (9): 1571-84. [PMID:25000480]

122. Yokota K, Shibata H, Kurihara I, Kobayashi S, Suda N, Murai-Takeda A, Saito I, Kitagawa H, Kato S, Saruta T et al.. (2007) Coactivation of the N-terminal transactivation of mineralocorticoid receptor by Ubc9. J Biol Chem, 282 (3): 1998-2010. [PMID:17105732]

123. Yuan J, Jia R, Bao Y. (2007) Aldosterone up-regulates production of plasminogen activator inhibitor-1 by renal mesangial cells. J Biochem Mol Biol, 40 (2): 180-8. [PMID:17394767]

124. Zennaro MC, Fernandes-Rosa F. (2017) 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations. J Endocrinol, 234 (1): T93-T106. [PMID:28348114]

125. Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombès M. (2001) A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol, 15 (9): 1586-98. [PMID:11518808]

126. Zhi L, Ringgenberg JD, Edwards JP, Tegley CM, West SJ, Pio B, Motamedi M, Jones TK, Marschke KB, Mais DE et al.. (2003) Development of progesterone receptor antagonists from 1,2-dihydrochromeno[3,4-f]quinoline agonist pharmacophore. Bioorg Med Chem Lett, 13 (12): 2075-8. [PMID:12781198]

127. Zhou MY, Gomez-Sanchez CE, Gomez-Sanchez EP. (2000) An alternatively spliced rat mineralocorticoid receptor mRNA causing truncation of the steroid binding domain. Mol Cell Endocrinol, 159 (1-2): 125-31. [PMID:10687858]

128. Ziera T, Irlbacher H, Fromm A, Latouche C, Krug SM, Fromm M, Jaisser F, Borden SA. (2009) Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel. FASEB J, 23 (11): 3936-46. [PMID:19567370]

Contributors

Show »« Hide

How to cite this page

Select citation format:

Mineralocorticoid receptor

Contents:

References

Contributors

How to cite this page