Table 1.
Vitamin D and VDR influence the expression and function of cell junction proteins.
| Tissues & Cell Types | TJ Proteins |
Cell Cultures In Vitro |
Experimental Models In Vivo |
Conclusions | References |
|---|---|---|---|---|---|
| Intestine | ZO-1 E-cadherin β-catenin |
T84 | The expression of VDR was positively correlated with the expression of ZO-1, occluding and claudin-5 in T84 cells. | [50] | |
| DLD-1 | VDR acts as a regulator in the expression of intestinal mucosal barrier proteins under hypoxia environment. The expressions of VDR, ZO-1, occludin, claudin-1, and E-cadherin were obviously higher in vitamin D plus hypoxia group than in single vitamin D treatment group. | [51] | |||
| SW480 | 1,25(OH)2D3 induced the expression of adhesion proteins and promoted the translocation of nuclear beta-catenin and ZO-1 to the plasma membrane. | [52] | |||
| Occludin | Cirrhotic rats | Vitamin D3 treatment significantly attenuated bacterial translocation and reduced intestinal permeability in thioacetamide-induced cirrhotic rats. It upregulated the expressions of occludin in the small intestine and claudin-1 in the colon of cirrhotic rats directly independent of intrahepatic status. Vitamin D3 treatment also enriched Muribaculaceae, Bacteroidales, Allobaculum, Anaerovorax, and Ruminococcaceae. | [53] | ||
| SW480-ADH | ROCK and MSK inhibition abrogates the induction of 1,25(OH)2D3 24-hydroxylase (CYP24), E-cadherin, and vinculin, and the repression of cyclin D1 by 1,25(OH)2D3. | [54] | |||
| Caco-2 | VDR−/− Mice |
1,25(OH)2D3 enhanced TJs by increasing junction protein expression and TER and preserved the structural integrity of TJs in the presence of DSS. VDR knockdown reduced the junction proteins and TER. 1,25(OH)2D3 can stimulate epithelial cell migration in vitro. | [43] | ||
| Claudins | Caco-2 SKCO15 | VDR−/− VDRΔIEC mice |
1,25(OH)2D3 treatment upregulates claudin-2 expression in human epithelium cells. VDR deletion in intestinal epithelial cells led to significant decreased claudin-2 expression. CLDN2 gene is a direct target of the transcription factor VDR. VDR enhances claudin-2 promoter activity in a Cdx1 binding, site-dependent manner. | [2] | |
| Enteroids Caco-2 SKCO15 |
VDR−/− Mice Salmonella- or DSS colitis model |
In inflamed intestines of Salmonella- or DSS-induced colitis model, a lack of VDR regulation led to a robust increase of claudin-2 at the mRNA and protein levels post-infection. In inflamed intestines of ulcerative colitis patients, VDR expression was low and claudin-2 was enhanced. In inflamed VDR−/− cells, 1,25(OH)2D3 enhanced claudin-2 promoter activity through the binding sites of NF-κB and STAT. | [27] | ||
| SKCO15 | O-VDR VDR∆IEC-Mice | Reduced claudin-15 was significantly correlated with decreased VDR in human IBD. O-VDR mice showed decreased susceptibility to chemically and bacterially induced colitis and marked increased claudin-15 expression in the colon. Correspondingly, colonic claudin-15 was reduced in VDR∆IEC mice, which were susceptible to colitis. Overexpression of intestinal epithelial VDR and vitamin D treatment resulted in significantly increased claudin-15. ChIP assays identified claudin-15 gene as a direct target of VDR. | [3] | ||
| Human Colonoids SKCO15 |
VDR−/− VDRΔIEC-mice |
Colonic VDR expression was low and significantly correlated with a reduction in claudin-5 in human CRC patients. Lack of VDR and a reduction of claudin-5 are associated with an increased number of tumors in the VDR−/− and VDRΔIEC mice. CHIP assay identified CLDN-5 as a downstream target of the VDR signaling pathway. | [4] | ||
| Human tissue microarr-ays | Vitamin D receptor (VDR) enhanced claudin-2 expression in colon and bile salt receptors VDR and Takeda G-protein coupled receptor 5 (TGR5) were highly expressed in esophageal adenocarcinoma and pre-cancerous lesions. | [23] | |||
| 1,25(OH)2D3 induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP(9k), and claudin-2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. | [55] | ||||
| SW480-ADH | 1,25(OH)2D3 activates the JMJD3 gene promoter and increases JMJD3 RNA in human cancer cells. JMJD3 knockdown or expression of an inactive mutant JMJD3 fragment decreased the induction by 1,25(OH)2D3 of several target genes and of an epithelial adhesive phenotype. It downregulated E-cadherin, claudin-1, and claudin-7. | [56] | |||
| calbindin-D9k−/− mutant mice | 1,25(OH)2D3 downregulates cadherin-17 and upregulates claudin-2 and claudin-12 in the intestine, suggesting that 1,25(OH)2D3 can route calcium through the paracellular path by regulating the epithelial cell junction proteins. | [57] | |||
| Caco-2 | VDR−/− mice | Claudin-2 and/or claudin-12-based TJs form paracellular Ca(2+) channels in intestinal epithelia. This study highlights a vitamin D-dependent mechanism in calcium homeostasis. | [1] | ||
| Barrier and mucosal immunity | Rat intestine |
The most strongly affected gene in intestine was CYP24 with 97-fold increase at 6 h post-1,25(OH)2D3 treatment. Intestinal calcium absorption genes: TRPV5, TRPV6, calbindin D(9k), and Ca(2+) dependent ATPase all were upregulated in response to 1,25(OH)2D3, However, a 1,25-(OH)2D3 suppression of several intra- and intercellular matrix modeling proteins, such as sodium/potassium ATPase, claudin-3, aquaporin 8, cadherin 17, and RhoA, suggesting a vitamin D regulation of TJ permeability and paracellular calcium transport. Expression of several other genes related to the immune system and angiogenesis was changed in response to 1,25(OH)2D3. | [58] | ||
| Caco-2 | C57BL/6 mice | 1,25(OH)2D3 pre-treatment ameliorated the ethanol-induced barrier dysfunction, TJ disruption, phosphorylation level of MLC, and generation of ROS, compared with ethanol-exposed monolayers. Mice fed with vitamin D-sufficient diet had a higher plasma level of 25(OH)D3 and were more resistant to ethanol-induced acute intestinal barrier injury compared with the vitamin D-deficient group. | [59] | ||
| VDRΔIEC VDRΔCEC Mice TNBS- colitis model |
Gut epithelial VDR deletion aggravates epithelial cell apoptosis, resulting in mucosal barrier permeability increases. | [60] | |||
| Caco-2 | DSS-colitis model | 1,25(OH)2D3 plays a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. | [61] | ||
| Lung | E-cadherin β-catenin |
A459 | Vitamin D pre-treatment reduced TGF-β and Wnt/β-catenin signaling by increasing p-VDR, protected from E-cadherin degradation and led to the regression of EMT (epithelial–mesenchymal transition)-mediated myofibroblast differentiation. | [62] | |
| 16HBE | Vitamin D is able to counteract the cigarette smoke extract-induced bronchial epithelial barrier disruption by TER (transepithelial electrical resistance) reduction inhibition, permeability increase, ERK phosphorylation increase, calpain-1 expression increase, and distribution anomalies and the cleavage of E-cadherin and β-catenin. | [63] | |||
| ZO-1 Occludin |
VDR−/− WTMice |
Vitamin D supplementation alleviated LPS-induced lung injury and preserved alveolar barrier function through maintenance of the pulmonary barrier by inducing expression of occludin and ZO-1 in whole lung homogenates. | [64] | ||
| Claudins | VDR−/− WT Mice |
VDR−/− mice showed significantly decreased ZO-1, occludin, claudin-1, claudin-2, claudin-4, claudin-10, β-catenin, and VE-cadherin expression in the lungs tissue compared with WT mice. | [65] | ||
| Kidney | ZO-1 | Rat | Rat treated with 1,25(OH)2D3 is able to abrogate podocytes injury, detected as desmin expression and loss of nephrin and ZO-1. | [66] | |
| Claudins | HEK 293 OK |
ICR mice | In kidney, 1,25(OH)2 VitD transcriptionally inhibits claudin-16 expression by a mechanism sensitive to CaSR and Mg2+. This renal effect of 1,25(OH)2 vitamin D may serve as an adaptive response to the 1,25(OH)2 vitamin D-induced increase in intestinal Mg2+ absorption. | [67] | |
| Cornea | ZO-1 Occludin |
VDR−/− WT Mice |
VDR−/− mice showed the decreased expression of ZO-1 and occludin, and changed ZO-distribution on corneas compared with WT mice. | [68] | |
| Corneal epithelium | Mouse, Rabbit, Human | Vitamin D enhances corneal epithelial barrier function. Cells showed increased TER, decreased IP, and increased occludin levels when cultured with 25(OH)D3 and 1,25(OH)2D3. | [69] | ||
| Skin | ZO-1 Claudins |
Human Psoriatic and Normal Skin |
Psoriatic skin reduced VDR, ZO-1, and claudin-1 expression compared to normal skin, and showed a significant correlation of downregulated VDR expression to claudin-1 and ZO-1. | [70] | |
| Brain | ZO-1 Occludin Claudins |
End.3 | Following hypoxic injury, 1,25(OH)2D3 treatment prevented decreased barrier function, and expression of zonula occludin-1, claudin-5, and occludin. VDR mediated the protective effect of 1,25(OH)2D3 against ischemic injury-induced blood–brain barrier dysfunction in cerebral endothelial cells. | [71] | |
| Oral | ZO-1 E-cadherin β-catenin |
HOK-16B | Vitamin D reinforces E-cadherin junctions by downregulating NF-κB signaling. In addition, vitamin D averts TNF-α-induced downregulation of the development of E-cadherin junctions in HGKs by decreasing the production of MMP-9, which was upregulated by TNF-α. | [72] | |
| Urinary bladder | Occludin Claudin-14 |
Mouse, Human |
During E. coli infection, vitamin D induced occludin and claudin-14 in mature superficial umbrella cells of the urinary bladder. Vitamin D increased cell–cell adhesion, thus consolidating the epithelial integrity during infection. | [73] |