Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses

Abstract

BackgroundSevere hypoglycemia induces brain edema by upregulating aquaporin-4 (AQP4) expression and by degrading tight junctions. Acute severe hypoglycemia induces a proinflammatory environment that may contribute to a disruption in the epithelial barrier by decreasing tight junction protein expression. Interestingly, the altered AQP4 expression has been considered to play a critical role in neuroinflammation during acute brain injury. It has been shown that AQP4 deletion reduces brain inflammation in AQP4-null mice after intracerebral LPS injection. However, the effect of AQP4 deletion regarding protection against hypoglycemia-induced blood-brain barrier (BBB) breakdown is unknown.MethodsAn acute severe hypoglycemic stress model was established via injection of 4 unit/kg body weight of insulin. Evans blue (EB) staining and water measurement were used to assess BBB permeability. Western blot, reverse transcription polymerase chain reaction, and immunofluorescence were used to detect the expression of related proteins. The production of cytokines was assessed via enzyme-linked immunosorbent assay.ResultsHypoglycemia-induced brain edema and BBB leakage were reduced in AQP4−/− mice. AQP4 deletion upregulated PPAR-γ and inhibited proinflammatory responses. Moreover, knockdown of aquaporin-4 by small interfering RNA in astrocytes co-cultured with endothelial cells effectively reduced transendothelial permeability and degradation of tight junctions. Treatment with PPAR-γ inhibitors showed that upregulation of PPAR-γ was responsible for the protective effect of AQP4 deletion under hypoglycemic conditions.ConclusionsOur data suggest that AQP4 deletion protects BBB integrity by reducing inflammatory responses due to the upregulation of PPAR-γ expression and attenuation of proinflammatory cytokine release. Reduction in AQP4 may be protective in acute severe hypoglycemia.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1203-8) contains supplementary material, which is available to authorized users.

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

“…Our data indicate that this upregulation of Aqp-4 is amplified in the SHRSP/FAD rat. A positive correlation between Aqp-4 and GFAP protein levels are consistent with prior reports of increased Aqp-4 corresponding with increased gliosis in a model of hypoglycemia (Zhao et al, 2018). Aqp-4 staining was redistributed to the neuropil, but it was unclear whether the loss of polarization was due to disintegration of vessels or retraction of endfeet.…”

Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury

“…Quite remarkably, these AQP4-null mice show substantially improved outcomes and survivability over their wild-type counterparts in four models of CNS injury: ischemic stroke (Manley et al, 2000;Yao et al, 2015A;Hirt et al, 2017), water intoxication (Manley et al, 2000), bacterial meningitis (Papadopoulos and Verkman 2005), and spinal-cord compression (Saadoun et al, 2008). AQP4-null mice have also shown reduced CE and BBB permeability in a model of severe hypoglycemia (Zhao et al, 2018). These studies represent a genetic proof-of-principle highlighting the central role of AQP4 in the formation of cerebral edema and its potential as a target for an anti-edema strategy aimed at stroke therapy.…”

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

“…AQP4 is abundantly expressed in astrocytic endfeet processes in direct contact with blood vessels 7‐9 . The specific highly polarized expression of AQP4 was suggested to play critical roles in maintaining cerebral water balance and BBB integrity 10‐13 . Previous studies have reported that AQP4 polarity was disturbed in various neurological diseases that cause brain edema and BBB disruption 14‐17 .…”