The retinoic acid receptor-related orphan receptor α positively regulates tight junction protein claudin domain-containing 1 mRNA expression in human brain endothelial cells

Abstract

Members of the claudin family play important roles in the formation of tight junctions (TJs) in several tissues. Claudin domain containing 1 (CLDND1) is homologous to this family and localizes to TJs and the cytoplasm when exogenously expressed in cultured epithelial cell lines. Furthermore, serum antibody levels of CLDND1-derived peptides are elevated in patients with cerebral infection, cardiovascular disease or diabetes mellitus as compared to healthy controls. However, CLDND1 transcriptional regulation remains poorly analyzed and most regional transcription factor binding sites remain to be defined. Notably, the CLDND1 promoter contains a putative response element for retinoic acid receptor-related orphan receptor α (RORα), which is involved in the above-mentioned disorders. In this study, we found that Cldnd1 and Rora mRNA levels are correlated in rat tissues and that RORα overexpression in human brain endothelial cells enhanced CLDND1 transcript expression. In addition, siRNA-mediated knockdown of RORα significantly decreased CLDND1 transcription. An electrophoresis mobility shift assay indicated that RORα binds to the identified response element in a sequence-specific manner. Furthermore, luciferase reporter assays confirmed that RORα interacts with the CLDND1 promoter to enhance transcription. Taken together, our findings strongly suggest that CLDND1 is a direct RORα target.

Deciphering GRINA/Lifeguard1: Nuclear Location, Ca2+ Homeostasis and Vesicle Transport

“…RORA shows a circadian expression and senses fatty acids, cholesterol, and oxysterols [95]. It is upregulated in the hippocampus of patients with Alzheimer’s disease [44] and also regulates the expression of the tight junction protein CLDND1 in human brain endothelial cells [96]. The cAMP responsive element binding protein 3-like 1 ( CREB3L1 ) gene codes for the membrane-bound ER stress transducer OASIS, which has an important role in osteoblast differentiation during bone development [97].…”

“…RORA shows a circadian expression and senses fatty acids, cholesterol, and oxysterols [95]. It is upregulated in the hippocampus of patients with Alzheimer’s disease [44] and also regulates the expression of the tight junction protein CLDND1 in human brain endothelial cells [96].…”

Retinoic acid receptor-related orphan receptor α reduces lipid droplets by upregulating neutral cholesterol ester hydrolase 1 in macrophages

“…In brain endothelial cells, claudin domain containing 1 (CLDND1), which is involved in tight junction formation, is regulated at the transcriptional level by RORα and at the post-transcriptional level by miR-124 [29,30]. Moreover, decreased CLDND1 expression in the adult murine cerebellum results in cerebellar hemorrhage [31].…”

Claudin‑1 silencing increases sensitivity of liver cancer HepG2 cells to 5‑fluorouracil by inhibiting autophagy

“…Tight junctions are a type of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and functioning as a physical barrier to prevent solutes and water from passing freely through the paracellular space (7). Tight junctions maintain cell polarity by preventing the lateral diffusion of integral membrane proteins between the lateral/basal and apical surfaces, allowing the specialized functions of each surface to be preserved (8). It has also been reported that tight junctions are associated with cellular survival, proliferation, migration and differentiation (9).…”