title: Excess salt exacerbates blood-brain barrier disruption via a p38/MAPK/SGK1-dependent pathway in permanent cerebral ischemia.
abstract: High salt diet (HSD) is one of the most important risk factors that contribute to many vascular diseases including ischemic stroke. One proposed mechanism underlying the disruption of blood-brain barrier (BBB) mediated by HSD is indirectly through enhancing blood pressure. The direct role of HSD on BBB integrity is unclear. Our purpose is to determine whether and how HSD might be involved in BBB breakdown during ischemia. To test that, we induced model of cerebral ischemia by permanent middle cerebral artery ligation (pMCAL) in either normal diet or HSD fed mice. We observed that HSD significantly enhanced ischemic brain damage which was associated with enhanced BBB disruption, increased leukocytes infiltration and loss of tight junction (TJ) proteins expression without apparently altering blood pressure. Our in vitro experiment also revealed that sodium chloride (NaCl) treatment down-regulated TJ protein expression by endothelial cells and substantially increased BBB permeability during starvation. Inhibition of p38/MAPK/SGK1 pathway eliminated the effect of NaCl on BBB permeability in vitro. In addition, we noticed a positive correlation between urinary sodium levels and ischemic lesion size in stroke patients. Together, our study demonstrates a hypertension-independent role of HSD during ischemia and provides rationale for post cerebral ischemic attack management.
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Tongshuai
authors.initials: T
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Myocardial Ischemia, The Second Affiliated Hospital of Harbin Medical University, Harbin, China 150081.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Cong
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Guangyou
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150081.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Lili
authors.initials: L
authors.lastname: Mu
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China 150081.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, Harbin Medical University, Harbin, China 150081.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Harbin Medical University, Harbin, China 150081.
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*; D020521:Stroke / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D020928:Mitogen-Activated Protein Kinases; D062793:Occludin; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D017673:Sodium Chloride, Dietary; D062725:Tight Junction Proteins; D062826:Zonula Occludens-1 Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases