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.

Keywords

• aldosterone
• hypertension
• intestine
• mineralocorticoids
• nuclear receptor
• sodium channels