Premium
Hyperglycemia‐increased activity of blood‐brain barrier Na‐K‐Cl cotransport and Na/H exchange involves SGK1 and PKCβII (893.35)
Author(s) -
Chechneva Olga,
Klug Nicholas,
Yuen Natalie,
O'Donnell Martha
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.893.35
Subject(s) - sgk1 , protein kinase c , endocrinology , astrocyte , cotransporter , medicine , chemistry , blood–brain barrier , stimulation , glucocorticoid , kinase , central nervous system , biochemistry , sodium , organic chemistry
Hyperglycemia (HG) exacerbates cerebral edema and worsens ischemic stroke outcome although the mechanisms are unclear. We have shown that ischemic factor stimulation of blood‐brain barrier (BBB) Na‐K‐Cl cotransport (NKCC) and Na/H exchange (NHE) increases secretion of Na and water into the brain, promoting cerebral edema formation. We recently found that HG (30 mM glucose; 6, 24,48 hr and 7 d) increases cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundance and activity and augments ischemic factor‐stimulated transporter activity. Serum‐glucocorticoid kinase 1 (SGK1) and protein kinase CβII (PKCβII) have been implicated in the pathogenesis of HG. Thus, here we examined whether SGK1 and PKCβII are involved in HG effects on BBB NKCC and NHE using cultured CMEC and Western blot, radioisotopic flux and microspectrofluorometry methods. HG (24 or 48 hr) significantly increased expression and activation of CMEC SGK1 and PKCβII. Inhibition of SGK1 or PKCβII with GSK650394 (10 μM) and CGP53353 (1 μM) respectively, reduced or abolished HG‐increased NKCC and NHE activity. In these studies we also found that HG (24 hr) significantly increased astrocyte NKCC activity in a manner reduced by SGK1 and PKCβII inhibitors. Our findings support the hypothesis that HG exacerbation of cerebral edema in ischemic stroke involves SGK1 and PKCβII‐induced increases in BBB and astrocyte Na transporter activities. Grant Funding Source : Supported by NIH and ADA