NF-YC Functions as a Corepressor of Agonist-bound Mineralocorticoid Receptor

Murai‐Takeda, Ayano; Shibata, Hirotaka; Kurihara, Isao; Kobayashi, Sakiko; Yokota, Kenichi; Suda, Norio; Mitsuishi, Yuko; Jo, Rie; Kitagawa, Hirochika; Kato, Shigeaki; Saruta, Takao; Itoh, Hiroshi

doi:10.1074/jbc.m109.053371

Cited by 32 publications

(14 citation statements)

References 39 publications

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“…Multiple factors regulate sodium balance; in this study, we focused on mineralocorticoid receptor (MR). In recent studies, we identified novel coregulators of MR3, 4 and proposed a new pathological condition associated with aberrant MR activation, designated MR‐associated hypertension 5…”

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confidence: 99%

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

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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BackgroundMineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation.Methods and ResultsWe generated IEC‐specific MR knockout (IEC‐MR‐KO) mice. With a standard diet, fecal sodium excretion was 1.5‐fold higher in IEC‐MR‐KO mice, with markedly decreased colonic expression of β‐ and γ‐epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC‐MR‐KO mice decreased by 30%, maintaining sodium balance; however, a low‐salt diet caused significant reductions in body weight and BP in IEC‐MR‐KO mice, and plasma aldosterone exhibited a compensatory increase. With a high‐salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC‐MR‐KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes.ConclusionsIntestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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confidence: 99%

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

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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“…In the case of the AR, of the 167 coregulators identified, only two are qualified as AR specific (Heemers & Tindall 2007). Of all the MR coregulators identified, ELL is the only MR-selective coactivator (Pascual-Le Tallec et al 2005), while NF-YC is the only selective corepressor (Murai-Takeda et al 2010) described to date. Notably, coregulators that bind nonspecifically may still display preference for one particular nuclear receptor.…”

Section: Discussionmentioning

confidence: 99%

GEMIN4 functions as a coregulator of the mineralocorticoid receptor

Yang¹,

Fuller²,

Morgan³

et al. 2015

Journal of Molecular Endocrinology

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The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily. Pathological activation of the MR causes cardiac fibrosis and heart failure, but clinical use of MR antagonists is limited by the renal side effect of hyperkalemia. Coregulator proteins are known to be critical for nuclear receptor-mediated gene expression. Identification of coregulators, which mediate MR activity in a tissue-specific manner, may allow for the development of novel tissue-selective MR modulators that confer cardiac protection without adverse renal effects. Our earlier studies identified a consensus motif among MR-interacting peptides, MPxLxxLL. Gem (nuclear organelle)-associated protein 4 (GEMIN4) is one of the proteins that contain this motif. Transient transfection experiments in HEK293 and H9c2 cells demonstrated that GEMIN4 repressed agonist-induced MR transactivation in a cell-specific manner. Furthermore, overexpression of GEMIN4 significantly decreased, while knockdown of GEMIN4 increased, the mRNA expression of specific endogenous MR target genes. A physical interaction between GEMIN4 and MR is suggested by their nuclear co-localization upon agonist treatment. These findings indicate that GEMIN4 functions as a novel coregulator of the MR.

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“…We have recently proposed such MR antagonist-responsive hypertension as "MR-associated hypertension" 10) and investigated the molecular actions of MR, among which we identified several novel coregulators of MR. 11,12) DM is a major cause of macro-and microvascular complications. The molecular mechanisms for those vascular complications have been explained by several moFrom the…”

Section: Discussionmentioning

confidence: 99%

“…8) It was reported that add-on treatment of an MR antagonist alleviated persistent albuminuria in DM patients with conventional antihypertensive treatment, 9) which suggests that aberrant MR activation could be also an underlying mechanism of hypertension in DM patients. We have recently proposed such MR antagonist-responsive hypertension as "MR-associated hypertension" 10) and investigated the molecular actions of MR, among which we identified several novel coregulators of MR. 11,12) DM is a major cause of macro-and microvascular complications. The molecular mechanisms for those vascular complications have been explained by several mo-HIGH GLUCOSE ACTIVATES MR THROUGH THE PKCβ2 lecular signaling, 13) including the polyol pathway, hexosamine biosynthetic pathway, and the PKC pathway under high glucose conditions.…”

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confidence: 99%

High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C β Signaling

et al. 2017

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SummaryActivation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCβ by TPA (12-OTetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCβ but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCβ by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCβ2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCβ signaling, which leads to MR stabilization and its transcriptional activities.( 3) which have elucidated that add-on therapy of MR antagonist is beneficial for the improvement of prognosis in heart failure patients, we became aware in recent decades that aberrant MR activation could be crucially involved in cardiovascular morbidity and mortality. Indeed it is prevalently known that primary aldosteronism, in which aldosterone excess causes hypertension through MR activation, increases the risk of cardiovascular events such as myocardial infarction and arrhythmia by three-to five-fold over essential hypertension.4) Additionally, add-on treatment of an MR antagonist has also been demonstrated to be effective in resistant hypertension (RHTN), 5) suggesting that activation of MR would play a key role on the progression of RHTN. These clinical findings has been driving many researchers to focus on the molecular mechanism of aberrant MR activation in RHTN and its related organ damages, but a detailed mechanism remains largely unknown.Hypertension is approximately twice as frequent in diabetes mellitus (DM) compared with non-DM patients 6) and RHTN is highly associated with DM, 7) but the etiology of hypertension and cardiovascular complications in DM patients is not fully understood.8) It was reported that add-on treatment of an MR antagonist alleviated persistent albuminuria in DM patients with conventional antihypertensive treatment, 9) which suggests that aberrant MR activation could be also an underlying mechanism of hypertension in DM patients. We have recently proposed such MR antagonist-responsive hypertension as "MR-associated hypertension" 10) and investigated the molecular actions of MR, among which we identified several novel coregulators of MR. 11,12) DM is a major cause of macro-and microvascular complications. The molecular mechanisms for those vascular complications have been explained by several moFrom the

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NF-YC Functions as a Corepressor of Agonist-bound Mineralocorticoid Receptor

Cited by 32 publications

References 39 publications

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

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

GEMIN4 functions as a coregulator of the mineralocorticoid receptor

High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C β Signaling

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