Abstract
Dietary NaCl depletion increases Na+ and Cl− absorption in the colon, but the mechanisms are not fully understood. So far, we reported that the expression of claudin-7 (CLDN7), a tight junction (TJ) protein, was upregulated in the mice fed with NaCl-depleted diets, but the regulatory mechanism has not been clarified. Here, we found that angiotensin II (ANGII) increases the mRNA level of CLDN7, which was inhibited by losartan, a type 1 ANGII (AT1) receptor antagonist. Immunofluorescence measurement showed that CLDN7 is colocalized with zonula occludens-1 at the TJ in untreated and ANGII-treated cells. ANGII decreased transepithelial electrical resistance (TER) and increased permeability to C1− without affecting permeability to lucifer yellow, a paracellular flux marker. In contrast, TER was increased by CLDN7 knockdown in the absence and presence of ANGII. ANGII increased the nuclear distribution of phosphorylated p65 subunit of NF-κB, which was inhibited by losartan. The ANGII-induced elevation of CLDN7 expression was blocked by BAY 11-7082 (BAY), an NF-κB inhibitor. Luciferase reporter assay showed that ANGII increases promoter activity of CLDN7, which was inhibited by the treatment with losartan or BAY, and introduction of mutations in κB-binding motifs in the promoter. The binding of p65 on the promoter region of CLDN7 was increased by ANGII, which was inhibited by losartan and BAY in chromatin immunoprecipitation assay. Our data suggest that ANGII acts on AT1 receptor and increases paracellular permeability to Cl− mediated by the elevation of CLDN7 expression in the colon.
Highlights
Most of electrolytes contained in foods and drinks are absorbed in the distal small intestine and colon [1]
Immunofluorescence measurement showed that the signal of CLDN7 is exaggerated by angiotensin II (ANGII) at the surface of the colonic epithelia (Figure 1B)
Serum aldosterone concentration was increased by NaCl depletion and aldosterone increased the mRNA and protein levels of CLDN2, but it did not change those of CLDN7 [10]
Summary
Most of electrolytes contained in foods and drinks are absorbed in the distal small intestine and colon [1]. ANGI is converted to ANGII by angiotensin-converting enzyme, resulting in the induction of arterial vasoconstriction, aldosterone secretion, and renal Na+ reabsorption. It has not been fully understood how circulating ANGII and aldosterone regulates the transport of electrolytes in the colon. We reported that both CLDN2 and CLDN7 expressions are upregulated in mice fed with NaCl-depleted diets [10]. Aldosterone increased CLDN2 expression in mouse colonic MCE301 cells without affecting CLDN7 expression Another factor may be involved in the upregulation of CLDN7 expression in NaCl depletion. We found that NaCl-depleted diets increase serum ANGII concentration in mice and ANGII increases the expression of CLDN7 in MCE301 cells. Our data indicate that ANGII may be involved in the paracellular absorption of Na+ and Cl− in the colon
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