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The Journal of Neuroscience, August 22, 2007, 27(34):9032-9042; doi:10.1523/JNEUROSCI.2088-07.2007

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Neurobiology of Disease
Angiotensin II Controls Occludin Function and Is Required for Blood–Brain Barrier Maintenance: Relevance to Multiple Sclerosis

Karolina Wosik,^1 * Romain Cayrol,^1 * Aurore Dodelet-Devillers,¹ France Berthelet,² Monique Bernard,¹ Robert Moumdjian,³ Alain Bouthillier,³ Timothy L. Reudelhuber,⁵ and Alexandre Prat^1,4,6

¹Neuroimmunology Research Laboratory, Center for Study of Brain Diseases, ²Department of Neuropathology, ³Department of Neurosurgery, ⁴Department of Neurology, ⁵Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, and ⁶Multiple Sclerosis Clinic, Department of Neurology, Centre Hospitalier de l'Université de Montréal-Notre Dame Hospital, University of Montreal, Montréal, Quebec, Canada H2L 4M1

Correspondence should be addressed to Dr. Alexandre Prat, Multiple Sclerosis Clinic and Neuroimmunology Research Laboratory, Centre Hospitalier de l'Université de Montréal-Notre Dame Hospital, 1560 Sherbrooke Street East, Montréal, Quebec, Canada H2L 4M1. Email: a.prat{at}umontreal.ca

The blood–brain barrier (BBB) restricts molecular and cellular trafficking between the blood and the CNS. Although astrocytes are known to control BBB permeability, the molecular determinants of this effect remain unknown. We show that angiotensinogen (AGT) produced and secreted by astrocytes is cleaved into angiotensin II (AngII) and acts on type 1 angiotensin receptors (AT₁) expressed by BBB endothelial cells (ECs). Activation of AT₁ restricts the passage of molecular tracers across human BBB-derived ECs through threonine-phosphorylation of the tight junction protein occludin and its mobilization to lipid raft membrane microdomains. We also show that AGT knock-out animals have disorganized occludin strands at the level of the BBB and a diffuse accumulation of the endogenous serum protein plasminogen in the CNS, compared with wild-type animals. Finally, we demonstrate a reduction in the number of AGT-immunopositive perivascular astrocytes in multiple sclerosis (MS) lesions, which correlates with a reduced expression of occludin similarly seen in the CNS of AGT knock-out animals. Such a reduction in astrocyte-expressed AGT and AngII is dependent, in vitro, on the proinflammatory cytokines tumor necrosis factor- and interferon-. Our study defines a novel physiological role for AngII in the CNS and suggests that inflammation-induced downregulation of AngII production by astrocytes is involved in BBB dysfunction in MS lesions.

Key words: astrocytes; tight junctions; renin-angiotensin system; CNS; neuroinflammation; lipid rafts; human; mouse; lymphocytes; immune privilege

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Received Feb. 27, 2007; revised June 1, 2007; accepted July 5, 2007.

Correspondence should be addressed to Dr. Alexandre Prat, Multiple Sclerosis Clinic and Neuroimmunology Research Laboratory, Centre Hospitalier de l'Université de Montréal-Notre Dame Hospital, 1560 Sherbrooke Street East, Montréal, Quebec, Canada H2L 4M1. Email: a.prat{at}umontreal.ca

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