| 1999 |
Claudin-5/TMVCF is an endothelial cell-specific component of tight junction (TJ) strands. When claudin-5 cDNA was introduced into mouse L fibroblasts, TJ strands were reconstituted that resembled those in endothelial cells in vivo (extracellular face-associated TJs), demonstrating that claudin-5 is sufficient to form TJ strands. |
Immunofluorescence microscopy, immunoreplica electron microscopy, and reconstitution of TJ strands in transfected mouse L fibroblasts |
The Journal of cell biology |
High |
10508865
|
| 2011 |
TNF-α reduces CLDN5 promoter activity and mRNA expression in mouse brain endothelial cells via NFκB signaling; overexpression of the NFκB subunit p65 (RelA) alone is sufficient to repress the Cldn5 promoter, and this regulation requires a conserved promoter region. |
Promoter-reporter assays, p65 overexpression, TNF-α treatment of primary brain endothelial cells isolated from C57BL/6 mice |
Cytokine |
Medium |
22138107
|
| 2012 |
The ETS transcription factor ERG directly regulates CLDN5 gene expression in endothelial cells. ERG knockdown reduces CLDN5 levels and increases endothelial permeability, with increased stress fibers and gap formation, placing ERG upstream of CLDN5 in the barrier-function pathway. |
ERG siRNA knockdown in endothelial cells, permeability assays, reporter/ChIP assays identifying CLDN5 as downstream ERG target |
The Journal of biological chemistry |
Medium |
22235125
|
| 2014 |
IL-1β induces downregulation of Cldn5 in brain microvascular endothelial cells (BMECs) via nuclear translocation of β-catenin and FoxO1, and this transcriptional repression is dependent on non-muscle myosin light chain kinase (nmMlck). Primary BMECs from nmMlck-null mice are resistant to IL-1β-induced Cldn5 repression. |
Primary BMECs from nmMlck-knockout mice, nuclear fractionation of β-catenin/FoxO1, barrier dysfunction assays, Cldn5 promoter analysis |
Journal of cell science |
High |
24522189
|
| 2020 |
Under hypoxia, CAV1 (caveolin-1) mediates redistribution of membranous CLDN5 into the cytosol in brain microvascular endothelial cells. Autophagy is then activated to degrade cytosolic aggregated CLDN5 and CAV1, thereby alleviating BBB breakdown. Genetic or pharmacological blockage of autophagy aggravates cytosolic CLDN5 aggregation and worsens BBB impairment. |
Zebrafish in vivo model, in vitro BMECs, genetic autophagy inhibition, pharmacological autophagy blockade, STED super-resolution microscopy, TEER measurements |
Autophagy |
High |
33280500
|
| 2022 |
A de novo G60R missense mutation in the first extracellular loop of claudin-5 converts the BBB tight junction from a barrier-forming to an anion-selective channel: stable cell lines expressing G60R claudin-5 still form tight junctions but display higher Cl⁻ permeability, lower Na⁺ permeability, and attenuated barrier against small molecules, establishing CLDN5-associated alternating hemiplegia as a channelopathy. |
Generation of stably transfected cell lines expressing wild-type or G60R claudin-5, ion permeability assays, protein modelling, sequence alignment |
Brain : a journal of neurology |
High |
35714222
|
| 2022 |
CLDN5 in podocytes acts as a regulator of WNT signaling: CLDN5 deletion reduces ZO1 expression and induces nuclear translocation of ZONAB, which transcriptionally downregulates WNT inhibitory factor-1 (WIF1), thereby activating WNT signaling and exacerbating podocyte injury and proteinuria. Podocyte-derived WIF1 also acts in a paracrine manner on tubular epithelial cells. |
Podocyte-specific Cldn5 knockout mice, diabetic nephropathy and ureteral obstruction models, nuclear fractionation of ZONAB, ChIP/reporter for WIF1 promoter, systemic WIF1 delivery |
Nature communications |
High |
35332151
|
| 2023 |
Blue light exposure causes rapid CLDN5 degradation in retinal endothelial cells via activation of ADAM17 metalloprotease. Under basal conditions ADAM17 is sequestered by the inhibitory G protein GNAZ; blue light disrupts this interaction, freeing ADAM17 to degrade CLDN5. Pharmacological or genetic inhibition of ADAM17 prevents CLDN5 degradation and preserves inner blood-retinal barrier integrity. |
Pharmacological ADAM17 inhibition, genetic ADAM17 knockdown, GNAZ knockdown, in vivo mouse blue-light exposure model, TEER/permeability assays, electroretinogram |
Fluids and barriers of the CNS |
High |
37095509
|
| 2017 |
The long isoform of human claudin-5 (303 aa, produced by the G allele of rs885985) is retained in intracellular compartments and does not localize to the plasma membrane or intercellular junctions, in contrast to the 218 aa isoform which traffics normally to junctions. Only the 218 aa form is detected in human lung tissue. |
Immunoblot of genotyped human lung tissue, forced expression of long vs. short isoforms in transfected cells, immunofluorescence localization |
Annals of the New York Academy of Sciences |
Medium |
28445614
|
| 2024 |
DLL4 (delta like 4) regulates endothelial CLDN5 expression through the NOTCH-NICD-RBPJ-CLDN5 signaling pathway. DLL4 deficiency in mice leads to persistent brain microvasculature abnormalities and increased vascular permeability both in vivo and in vitro, and neonatal hyperoxia reduces both DLL4 and CLDN5 expression in developing mouse brain endothelial cells. |
Dll4+/LacZ heterozygous mice, in vitro human brain microvascular endothelial cells, Notch pathway inhibition, vascular permeability assays, in vivo hyperoxia model |
The Journal of physiology |
Medium |
38632887
|
| 2025 |
In adipocytes, CLDN5 regulates subcellular localization of Y-box protein 3 (YBX3), which directly controls IL10 expression by binding to the IL10 promoter and 3'-UTR. CLDN5 ablation in adipocytes impairs thermogenesis and energy expenditure; this effect is mediated paracrinally through IL10 signaling (via IL10R) on neighboring thermogenic adipocytes. |
Adipocyte-specific Cldn5 knockout mice, gene expression profiling, ChIP/reporter assays for YBX3 binding to IL10 promoter, paracrine co-culture experiments, metabolic phenotyping |
Nature communications |
High |
40610440
|
| 2026 |
CLDN5 forms a stable complex with β1-integrin in podocytes via its intracellular loop and C-terminal domains, binding the intracellular domain of β1-integrin. This interaction prevents HUWE1-mediated ubiquitination of β1-integrin at lysine K774 and subsequent proteasomal degradation, while also ensuring proper membrane localization of β1-integrin. CLDN5 deletion impairs podocyte adhesion, spreading, and resistance to mechanical stress. |
Super-resolution imaging, Co-immunoprecipitation, domain-mapping mutagenesis, ubiquitination assays, Cldn5-KO mice with hypertensive and adriamycin injury models |
The Journal of biological chemistry |
High |
41539562
|
| 2025 |
Homocysteine (HCY) suppresses Cldn5 transcription by promoting H3K27me3 enrichment at the Cldn5 promoter. High-intensity interval training (HIIT) reverses this by reducing HCY levels and restoring expression of ETS1, a transcriptional activator of Cldn5, thereby re-establishing BBB integrity and alleviating cognitive impairment. |
CUMS and HHCY mouse models, ChIP for H3K27me3 at Cldn5 promoter, RT-qPCR, behavioral testing, metabolic enzyme expression analysis |
Neurobiology of stress |
Medium |
41035457
|
| 2025 |
Molecular dynamics simulations of multi-pore claudin-5 complexes (16 protomers, 3 adjacent pores) show that the multi-Pore I structural model recapitulates the anion-selective permeability phenotype of the G60R CLDN5 variant. Free energy calculations reveal that ion passage is hindered by higher barriers in multi-pore than in single-pore architectures. |
All-atom molecular dynamics simulation, free energy calculations of water and ion permeation across wild-type and G60R claudin-5 multi-pore models |
bioRxivpreprint |
Low |
|