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

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 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.

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.

• Authors: Toshifumi Nakamura, Isao Kurihara, Sakiko Kobayashi, Kenichi Yokota, Ayano Murai-Takeda, Yuko Mitsuishi, Mitsuha Morisaki, Nao Kohata, Yosuke Oshima, Yukiko Minami, Hirotaka Shibata, Hiroshi Itoh
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 7 Issue 13 (06 21 2018) ISSN: 2047-9980 [Electronic] England
• PMID: 29929989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Chemical References

• Antihypertensive Agents
• Epithelial Sodium Channels
• Mineralocorticoid Receptor Antagonists
• Nr3c2 protein, mouse
• Receptors, Mineralocorticoid
• Sodium Chloride, Dietary
• Aldosterone

Topics

• Aldosterone (metabolism)
• Animals
• Antihypertensive Agents (pharmacology)
• Blood Pressure (drug effects)
• Colon (drug effects, metabolism)
• Diet, Sodium-Restricted
• Disease Models, Animal
• Epithelial Sodium Channels (genetics, metabolism)
• Feces (chemistry)
• Hypertension (genetics, metabolism, physiopathology, prevention & control)
• Intestinal Absorption (drug effects)
• Intestinal Elimination
• Intestinal Mucosa (drug effects, metabolism)
• Male
• Mice, Knockout
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Receptors, Mineralocorticoid (deficiency, genetics, metabolism)
• Renal Elimination
• Sodium Chloride, Dietary (metabolism, urine)