RGD Reference Report - Poldip2 mediates blood-brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model. - Rat Genome Database

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Poldip2 mediates blood-brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model.

Authors: Gao, Meng  Lu, Weitian  Shu, Yue  Yang, Zhengyu  Sun, Shanquan  Xu, Jin  Gan, Shengwei  Zhu, Shujuan  Qiu, Guoping  Zhuo, Fei  Xu, Shiye  Wang, Yiying  Chen, Junhong  Wu, Xuan  Huang, Juan 
Citation: Gao M, etal., CNS Neurosci Ther. 2020 Dec;26(12):1288-1302. doi: 10.1111/cns.13446. Epub 2020 Aug 12.
RGD ID: 124713556
Pubmed: PMID:32790044   (View Abstract at PubMed)
PMCID: PMC7702237   (View Article at PubMed Central)
DOI: DOI:10.1111/cns.13446   (Journal Full-text)


BACKGROUND: Specific highly polarized aquaporin-4 (AQP4) expression is reported to play a crucial role in blood-brain barrier (BBB) integrity and brain water transport balance. The upregulation of polymerase δ-interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2-mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss.
METHODS AND RESULTS: Mouse BM model was induced by injecting mice with group B hemolytic streptococci via posterior cistern. Recombinant human Poldip2 (rh-Poldip2) was administered intranasally at 1 hour after BM induction. Small interfering ribonucleic acid (siRNA) targeting Poldip2 was administered by intracerebroventricular (i.c.v) injection at 48 hours before BM induction. A specific inhibitor of matrix metalloproteinases (MMPs), UK383367, was administered intravenously at 0.5 hour before BM induction. Western blotting, immunofluorescence staining, quantitative real-time PCR, neurobehavioral test, brain water content test, Evans blue (EB) permeability assay, transmission electron microscopy (TEM), and gelatin zymography were carried out. The results showed that Poldip2 was upregulated and AQP4 polarity was lost in mouse BM model. Both Poldip2 siRNA and UK383367 improved neurobehavioral outcomes, alleviated brain edema, preserved the integrity of BBB, and relieved the loss of AQP4 polarity in BM model. Rh-Poldip2 upregulated the expression of MMPs and glial fibrillary acidic protein (GFAP) and downregulated the expression of β-dystroglycan (β-DG), zonula occludens-1 (ZO-1), occludin, and claudin-5; whereas Poldip2 siRNA downregulated the expression of MMPs and GFAP, and upregulated β-DG, ZO-1, occludin, and claudin-5. Similarly, UK383367 downregulated the expression of GFAP and upregulated the expression of β-DG, ZO-1, occludin, and claudin-5.
CONCLUSION: Poldip2 inhibition alleviated brain edema and preserved the integrity of BBB partially by relieving the loss of AQP4 polarity via MMPs/β-DG pathway.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
streptococcal meningitis treatmentISOPoldip2 (Mus musculus)124713556; 124713556 RGD 
streptococcal meningitis treatmentIMP 124713556 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Poldip2  (DNA polymerase delta interacting protein 2)

Genes (Mus musculus)
Poldip2  (polymerase (DNA-directed), delta interacting protein 2)

Genes (Homo sapiens)
POLDIP2  (DNA polymerase delta interacting protein 2)


Additional Information