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

Abstract

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.

Biglycan Is a Novel Mineralocorticoid Receptor Target Involved in Aldosterone/Salt-Induced Glomerular Injury

“…The MR is activated by the steroid hormone aldosterone, as well as by corticosteroids, when the protecting enzyme 11b-hydroxysteroid dehydrogenase type 2 (HSD2) is not co-expressed. Its main function in the kidneys and colon is to regulate sodium balance and blood pressure [ 1 , 2 , 3 ]. Over the last two decades, several clinical trials have revealed the beneficial effects of MR antagonists (MRAs) in improving the prognosis of cardiovascular disease [ 4 , 5 , 6 ].…”

The role of NHE3 (Slc9a3) in oxalate and sodium transport by mouse intestine and regulation by cAMP

“…NHE3 KO mice are known to have high serum aldosterone (Schultheis, Clarke, Meneton, Miller, et al, 1998). Aldosterone targets the colon through mineralocorticoid receptor (MR) to regulate sodium absorption through NHE3 and ENaC (Nakamura et al, 2018). The NHE3 KO mouse has upregulated expression of the β and γ subunits of ENaC (Schultheis, Clarke, Meneton, Miller, et al, 1998) as do rats with chronic renal failure (Hatch & Freel, 2008).…”

Upregulation of Claudin-7 Expression by Angiotensin II in Colonic Epithelial Cells of Mice Fed with NaCl-Depleted Diets

“…The expression of CLDN2, which forms cation-permeable pore, is upregulated by aldosterone mediated through the activation of the mineralocorticoid receptor. The intestinal mineralocorticoid receptor has been recently reported to be involved in the regulation of Na + absorption in the colon using intestinal epithelial cell (IEC)-specific knockout mice [16]. CLDN2 may be involved in the regulation of NaCl absorption by aldosterone.…”