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

Meng Gao; Weitian Lu; Yue Shu; Zhengyu Yang; Shanquan Sun; Jin Xu; Shengwei Gan; Shujuan Zhu; Guoping Qiu; Fei Zhuo; Shiye Xu; Yiying Wang; Junhong Chen; Xuan Wu; Juan Huang

doi:10.1111/cns.13446

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

CNS Neurosci Ther. 2020 Dec;26(12):1288-1302. doi: 10.1111/cns.13446. Epub 2020 Aug 12.

Authors

Meng Gao¹, Weitian Lu^{1

2}, Yue Shu¹, Zhengyu Yang¹, Shanquan Sun^{1

2}, Jin Xu^{1

2}, Shengwei Gan^{1

2}, Shujuan Zhu^{1

2}, Guoping Qiu^{1

2}, Fei Zhuo^{1

2}, Shiye Xu^{1

2}, Yiying Wang¹, Junhong Chen¹, Xuan Wu³, Juan Huang^{1

2}

Affiliations

¹ Department of Anatomy, Chongqing Medical University, Chongqing, China.
² Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
³ Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

Abstract

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.

Keywords: AQP4; MMPs; Poldip2; bacterial meningitis; blood-brain barrier; cerebral edema.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intranasal
Animals
Aquaporin 4 / biosynthesis*
Aquaporin 4 / genetics
Blood-Brain Barrier / metabolism*
Blood-Brain Barrier / pathology
Brain Edema / genetics
Brain Edema / metabolism*
Brain Edema / pathology
Disease Models, Animal*
Humans
Male
Meningitis, Bacterial / genetics
Meningitis, Bacterial / metabolism*
Meningitis, Bacterial / pathology
Mice
Mitochondrial Proteins / biosynthesis*
Mitochondrial Proteins / deficiency
Mitochondrial Proteins / genetics
Nuclear Proteins / biosynthesis*
Nuclear Proteins / deficiency
Nuclear Proteins / genetics

Substances

Aqp4 protein, mouse
Aquaporin 4
Mitochondrial Proteins
Nuclear Proteins
mitogenin 1 protein, mouse