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

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Mineralocorticoid receptor ( <jats:styled-content style="fixed-case">MR</jats:styled-content> ) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of <jats:styled-content style="fixed-case">MR</jats:styled-content> in intestinal epithelial cells ( <jats:styled-content style="fixed-case">IECs</jats:styled-content> ) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal <jats:styled-content style="fixed-case">MR</jats:styled-content> is expected to have essential roles in blood pressure (BP) regulation. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> We generated <jats:styled-content style="fixed-case">IEC</jats:styled-content> ‐specific <jats:styled-content style="fixed-case">MR</jats:styled-content> knockout ( <jats:styled-content style="fixed-case">IEC</jats:styled-content> ‐ <jats:styled-content style="fixed-case">MR</jats:styled-content> ‐ <jats:styled-content style="fixed-case">KO</jats:styled-content> ) mice. With a standard diet, fecal sodium excretion was 1.5‐fold higher in <jats:styled-content style="fixed-case">IEC</jats:styled-content> ‐ <jats:styled-content style="fixed-case">MR</jats:styled-content> ‐ <jats:styled-content style="fixed-case">KO</jats:styled-content> mice, with markedly decreased colonic expression of β‐ and γ‐epithelial sodium channel, than in control mice. Urinary sodium excretion in <jats:styled-content style="fixed-case">IEC</jats:styled-content> ‐ <jats:styled-content style="fixed-case">MR</jats:styled-content> ‐ <jats:styled-content style="fixed-case">KO</jats:styled-content> mice decreased by 30%, maintaining sodium balance; however, a low‐salt diet caused significant reductions in body weight and BP in <jats:styled-content style="fixed-case">IEC</jats:styled-content> ‐ <jats:styled-content style="fixed-case">MR</jats:styled-content> ‐ <jats:styled-content style="fixed-case">KO</jats:styled-content> 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 <jats:styled-content style="fixed-case">IEC</jats:styled-content> ‐ <jats:styled-content style="fixed-case">MR</jats:styled-content> ‐ <jats:styled-content style="fixed-case">KO</jats:styled-content> mice than in control mice. The addition of the <jats:styled-content style="fixed-case">MR</jats:styled-content> antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> Intestinal <jats:styled-content style="fixed-case">MR</jats:styled-content> 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 <jats:styled-content style="fixed-case">MR</jats:styled-content> is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases. </jats:p> </jats:sec>