High glucose-induced effects on Naþ -Kþ -2Cl-cotransport and Naþ /Hþ exchange of blood-brain barrier endothelial cells: Involvement of SGK1, PKCbII, and SPAK/OSR1

Nicholas R. Klug, Olga V. Chechneva, Benjamin Y. Hung, Martha E. O'Donnell

Research output: Contribution to journalArticlepeer-review

Abstract

Hyperglycemia exacerbates edema formation and worsens neurological outcome in ischemic stroke. Edema formation in the early hours of stroke involves transport of ions and water across an intact blood-brain barrier (BBB), and swelling of astrocytes. We showed previously that high glucose (HG) exposures of 24 hours to 7 days increase abundance and activity of BBB Naþ -K þ - 2Cl- cotransport (NKCC) and Naþ /H þ exchange 1 (NHE1). Further, bumetanide and HOE-642 inhibition of these transporters significantly reduces edema and infarct following middle cerebral artery occlusion in hyperglycemic rats, suggesting that NKCC and NHE1 are effective therapeutic targets for reducing edema in hyperglycemic stroke. The mechanisms underlying hyperglycemia effects on BBB NKCC and NHE1 are not known. In the present study we investigated whether serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCbII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCbII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCbII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCbII abundance or phosphorylation (activity) after 24 or 48 h HG exposures. Further, we found that HG-induced increases in NKCC and NHE1 abundance were abolished by inhibition of SGK1 but not PKCbII, whereas the increases in NKCC and NHE activity were abolished by inhibition of either kinase. Finally, we found evidence that STE20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 (SPAK/OSR1) participate in the HG-induced effects on BBB NKCC.

Original languageEnglish (US)
Pages (from-to)C619-C634
JournalAmerican Journal of Physiology - Cell Physiology
Volume320
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Blood-brain barrier
  • Hyperglycemia
  • PKCb
  • SGK-1
  • SPAK/OSR1

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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