Abstract
Dietary NaCl depletion increases Na+ absorption and K+ secretion in the colon, but the mechanisms are not fully understood. In mice fed with NaCl-depleted diets, the expression of claudin-2 and -7 increased compared to those in control mice. Aldosterone (ALD) concentration was also increased. We examined the regulatory mechanism of claudin expression by ALD using the murine colonic epithelial MCE301 cells. ALD dose-dependently increased claudin-2 expression without affecting the expression of claudin-4, -7, -8, and -15. ALD increased nuclear distribution of mineralocorticoid receptor (MR), which was inhibited by spironolactone, an MR antagonist. The ALD-induced elevation of claudin-2 mRNA and protein expression was inhibited by spironolactone, but not by RU-486, a glucocorticoid receptor antagonist. Luciferase reporter assay showed that ALD interacts with the promoter region between -2,021 and -2,008 of human claudin-2. The binding of MR on the promoter region of claudin-2 was increased by ALD, which was inhibited by spironolactone in chromatin immunoprecipitation assay. Our data suggest that ALD acts on MR and increases paracellular permeability to ions mediated by the elevation of claudin-2 expression in the colon. NaCl depletion may increase ALD secretion from adrenal cortex, resulting in the elevation of paracellular permeability to cations in the colon.
Highlights
The net flux rates of Na+, K+, Cl− and HCO3− in the colon vary according to the concentration in the lumen[1]
ALD increased the expression of claudin-2, which was blocked by spironolactone, an mineralocorticoid receptor (MR) antagonist, in the murine colonic epithelial MCE301 cells
NaCl depletion significantly increased the protein levels of claudin-2 and -7, whereas it did not change those of claudin-4, -8, and -15, MR, and glucocorticoid receptor (GR) in the colon (Fig. 1A–C)
Summary
The net flux rates of Na+, K+, Cl− and HCO3− in the colon vary according to the concentration in the lumen[1]. ALD increases Na+ absorption in both proximal and distal segments, but the mechanism of ALD is different in these segments[5]. ALD increases amiloride-insensitive Na+ absorption accompanied by unchangeable potential difference and slight elevation of short circuit current (Isc) in proximal colon. ALD increases amiloride-sensitive Na+ absorption accompanied by an elevation of transmural potential and Isc in distal colon. A segment specific expression pattern of claudins determines the tightness of the TJs from proximal to distal segments. Both claudin-2 and -15 forms a cation permeable pore, but the expression pattern is different. ALD increased the expression of claudin-2, which was blocked by spironolactone, an MR antagonist, in the murine colonic epithelial MCE301 cells. Up-regulation of claudin-2 may be involved in the ALD-induced cation transport in the colon
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