Alteration of Tight Junction Gene Expression by Calcium- and Vitamin D-Deficient Diet in the Duodenum of Calbindin-Null Mice

Abstract

Calcium absorption is regulated by both active (transcellular) and passive (paracellular) pathways. Although each pathway has been studied, correlations between the two pathways have not been well elucidated. In previous investigations, the critical transcellular proteins, calbindin-D9k (CaBP-9k) and -D28k (CaBP-28k), were shown to affect other transcellular pathways by buffering intracellular calcium concentrations. The rate of paracellular calcium transport in the duodenum is generally determined by the expression of tight junction genes. In the present study, the effect of dietary calcium and/or vitamin D supplementation on the expression of tight junction genes (occludin, ZO-1 and claudin 2, 10b, 12 and 15) in the duodenum of CaBP-9k- and/or -28k-deficient mice was examined. With a normal diet, the expression of most tight junction genes in the duodenum was significantly increased in CaBP-9k knockout (KO) mice compared to wild-type (WT) animals. With a calcium- and vitamin D-deficient diet, tight junction gene expression was significantly decreased in the duodenum of the CaBP-9k KO mice. These findings suggest that expression of paracellular tight junction genes is regulated by transcellular CaBP proteins, suggesting that active and passive calcium transport pathways may function cooperatively.

Vitamin D-Enhanced Duodenal Calcium Transport

“…In vivo experiment also revealed downregulation of claudin-2 and -12 in the duodenum, ileum, and colon of the VDR knockout mice at both transcriptional and translational levels (Fujita et al, 2008). Similarly, Hwang et al (2013) showed downregulation of claudin-2 as well as claudin-15 mRNAs and proteins in the duodenum of calcium/vitamin D-deficient calbindin-D 9k knockout mice. On the other hand, high concentration of 1,25(OH) 2 D 3 conversely suppressed claudin-3 mRNA expression in the rat duodenum as determined by Affymetrix microarrays (Kutuzova & DeLuca, 2004).…”

“…1,25(OH) 2 D 3 also modulates the expression of duodenal nonclaudin tight junction-related proteins, such as zonula occludens protein (ZO) and occludin (Hwang et al, 2013). Hwang et al (2013) found the expressions of occludin and ZO-1 transcripts to be downregulated in calbindin-D 9k knockout mice given calcium-and vitamin D-deficient diet, but not normal diet. Western blot and immunohistochemical analyses of ZO-1 in duodenum also showed similar trend as mRNA results.…”

“…In addition, other charge-selective claudins, such as claudin-10 and -16, the latter of which has been reported to be calcium-permeable and is expressed in the rat small intestine, may have roles in calcium absorption (Inai et al, 2005;Wongdee, Teerapornpuntakit, Siangpro, Chaipai, & Charoenphandhu, 2013). 1,25(OH) 2 D 3 also modulates the expression of duodenal nonclaudin tight junction-related proteins, such as zonula occludens protein (ZO) and occludin (Hwang et al, 2013). Hwang et al (2013) found the expressions of occludin and ZO-1 transcripts to be downregulated in calbindin-D 9k knockout mice given calcium-and vitamin D-deficient diet, but not normal diet.…”

Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity

“…Our diet was low in calcium and vitamin D, both needed for tight junction physiology. In the calbindin-null mice, a calcium and vitamin D deficient diet resulted in down-regulation of tight junction genes (32). Tight junction protein expression is regulated through ERK1/2 and AKT signaling (33,34), both of which were clearly down-regulated in our WD mice.…”

Intestinal absorption and renal reabsorption of calcium throughout postnatal development

“…40 Further, compensatory increases in Cldn2 and Cldn15 were observed in the duodenum of adult CaBP9k KO mice, suggesting the possibility of a cooperative interaction between the transcellular and paracellular calcium absorption pathways. 46 …”