title: Hypoxia-inducible factor-1α contributes to brain edema after stroke by regulating aquaporins and glycerol distribution in brain.
abstract: Brain edema following stroke is a critical clinical problem due to its association with increased morbidity and mortality. Despite its significance, present treatment for brain edema simply provides symptomatic relief due to the fact that molecular mechanisms underlying brain edema remain poorly understood. The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α) and aquaporins (AQP-4 and -9) in regulating cerebral glycerol accumulation and inducing brain edema in a rodent model of stroke. Two-hours of middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in male Sprague-Dawley rats (250-280 g). Anti-AQP-4 antibody, anti-AQP-9 antibody, or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) was given at the time of MCAO. The rats were sacrificed at 1 and 24 hours after reperfusion and their brains were examined. Extracellular and intracellular glycerol concentration of brain tissue was calculated with an enzymatic glycerol assay. The protein expressions of HIF-1α, AQP-4 and AQP-9 were determined by Western blotting. Brain edema was measured by brain water content. Compared to control, edema (p < 0.01), increased glycerol (p < 0.05), and enhanced expressions of HIF-1α, AQP-4, and AQP-9 (p < 0.05) were observed after stroke. With inhibition of AQP-4, AQP-9 or HIF-1α, edema and extracellular glycerol were significantly (p < 0.01) decreased while intracellular glycerol was increased (p < 0.01) 1 hour after stroke. Inhibition of HIF-1α with 2ME2 suppressed (p < 0.01) the expression of AQP-4 and AQP-9. These findings suggest that HIF-1α serves as an upstream regulator of cerebral glycerol concentrations and brain edema via a molecular pathway involving AQP-4 and AQP-9. Pharmacological blockade of this pathway in stroke patients may provide novel therapeutic strategies.
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Higashida
authors.forename: Changya
authors.initials: C
authors.lastname: Peng
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Dornbos
authors.forename: Kailing
authors.initials: K
authors.lastname: Teng
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Harish
authors.initials: H
authors.lastname: Kinni
authors.forename: Murali
authors.initials: M
authors.lastname: Guthikonda
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D020346:Aquaporins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C496032:Aqp4 protein, rat; C491637:Aqp9 protein, rat; D051401:Aquaporin 4; D020346:Aquaporins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005990:Glycerol