title: Ischemic factor-induced increases in cerebral microvascular endothelial cell Na/H exchange activity and abundance: evidence for involvement of ERK1/2 MAP kinase.
abstract: Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl, and water into the brain across an intact blood-brain barrier (BBB), together with swelling of astrocytes as they take up the ions and water crossing the BBB. Our previous studies provide evidence that luminal BBB Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC) are rapidly stimulated by the ischemic factors hypoxia, aglycemia, and AVP, and inhibition of NKCC and NHE activities by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. We examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundance. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemic factors. We found that hypoxia, aglycemia, and AVP increase CMEC NHE activity through 5 h and that NHE1, but not NHE2, abundance is increased by 1- to 5-h exposures to these factors. Furthermore, we found that these factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities.
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California.
authors.forename: Natalie
authors.initials: N
authors.lastname: Yuen
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California.
authors.forename: Tina I
authors.initials: TI
authors.lastname: Lam
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California.
authors.forename: Breanna K
authors.initials: BK
authors.lastname: Wallace
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Klug
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Anderson
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California meodonnell@ucdavis.edu.
authors.forename: Martha E
authors.initials: ME
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D017923:Sodium-Hydrogen Exchangers; D001127:Arginine Vasopressin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose; D010100:Oxygen
keywords: ERK1/2 MAP kinase; FR180204; HOE642; blood-brain barrier; cerebral edema; stroke