Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation

Toshifumi Nakamura, Isao Kurihara, Sakiko Kobayashi, Kenichi Yokota, Ayano Takeda, Yuko Mitsuishi, Mitsuha Morisaki, Nao Kohata, Yosuke Oshima, Yukiko Minami, Hirotaka Shibata, Hiroshi Itoh

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background-—Mineralocorticoid 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 Results-—We 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 b- and c-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. Conclusions-—Intestinal 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.

Original languageEnglish
Article numbere008259
JournalJournal of the American Heart Association
Volume7
Issue number13
DOIs
Publication statusPublished - 2018 Jul 1

Fingerprint

Mineralocorticoid Receptors
Intestinal Absorption
Sodium
Blood Pressure
Epithelial Cells
Epithelial Sodium Channels
Desoxycorticosterone
Salts
Genotype
Diet
Mineralocorticoid Receptor Antagonists
Sodium-Restricted Diet
Spironolactone
Aldosterone
Knockout Mice
Muscle Cells
Smooth Muscle Myocytes
Intestines
Colon
Cardiovascular Diseases

Keywords

  • Aldosterone
  • Hypertension
  • Intestine
  • Mineralocorticoids
  • Nuclear receptor
  • Sodium channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation. / Nakamura, Toshifumi; Kurihara, Isao; Kobayashi, Sakiko; Yokota, Kenichi; Takeda, Ayano; Mitsuishi, Yuko; Morisaki, Mitsuha; Kohata, Nao; Oshima, Yosuke; Minami, Yukiko; Shibata, Hirotaka; Itoh, Hiroshi.

In: Journal of the American Heart Association, Vol. 7, No. 13, e008259, 01.07.2018.

Research output: Contribution to journalArticle

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abstract = "Background-—Mineralocorticoid 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 Results-—We 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 b- and c-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. Conclusions-—Intestinal 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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author = "Toshifumi Nakamura and Isao Kurihara and Sakiko Kobayashi and Kenichi Yokota and Ayano Takeda and Yuko Mitsuishi and Mitsuha Morisaki and Nao Kohata and Yosuke Oshima and Yukiko Minami and Hirotaka Shibata and Hiroshi Itoh",
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T1 - Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation

AU - Nakamura, Toshifumi

AU - Kurihara, Isao

AU - Kobayashi, Sakiko

AU - Yokota, Kenichi

AU - Takeda, Ayano

AU - Mitsuishi, Yuko

AU - Morisaki, Mitsuha

AU - Kohata, Nao

AU - Oshima, Yosuke

AU - Minami, Yukiko

AU - Shibata, Hirotaka

AU - Itoh, Hiroshi

PY - 2018/7/1

Y1 - 2018/7/1

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AB - Background-—Mineralocorticoid 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 Results-—We 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 b- and c-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. Conclusions-—Intestinal 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.

KW - Aldosterone

KW - Hypertension

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KW - Mineralocorticoids

KW - Nuclear receptor

KW - Sodium channels

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