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Cited by 21Barrier Structure and Function StudiesIon Transport and Channel RegulationAcute Ischemic Stroke Management

High glucose-induced effects on Na+-K+-2Cl− cotransport and Na+/H+ exchange of blood-brain barrier endothelial cells: involvement of SGK1, PKCβII, and SPAK/OSR1

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Klug, Nicholas R., Chechneva, Olga V., Hung, Benjamin Y., O’Donnell, Martha E.·2021·American Journal of Physiology-Cell Physiology
DOI 10.1152/ajpcell.00177.2019PMC PMC8260356
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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 Na+-K+-2Cl− cotransport (NKCC) and Na+/H+ 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 (PKCβII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCβII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCβII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCβII 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 PKCβII, 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.

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  • SGK1 impacts blood pressure regulation, with significant effect within the blood-brain barrier.

    “SGK1 impacts blood pressure regulation. This effect is significant within the blood-brain barrier”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Klug et al., 2021

    The Discussion reports that SGK1 contributes to high-glucose-induced changes in ion transport in blood-brain barrier endothelial cells. It does not report an effect on blood pressure regulation; searches for blood pressure and hypertension found no such finding in our copy. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Klug, N. R., Chechneva, O. V., Hung, B. Y., & O’Donnell, M. E.
Affiliations
University of California, Davis (US)
Corresponding author
O’Donnell, Martha E.
ORCID
Venue
American Journal of Physiology-Cell Physiology
Publisher
American Physiological Society
Published
2021-04-01
Volume
320
Issue
4
Pages
C619-C634
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
DOI
10.1152/ajpcell.00177.2019
PMC
PMC8260356
OpenAlex
W3119160690
Cited by
21
References
0
Citations by year
2026: 1 · 2025: 3 · 2024: 9 · 2023: 2 · 2022: 2 · 2021: 4
FWCI
1.70
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (14PRE19830035)
  • HHS | National Institutes of Health (NS039953)
  • American Diabetes Association Research Foundation (1-13-BS-135)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Keywords
hyperglycemia, blood-brain barrier, Na+-K+-2Cl- cotransport, NKCC, NHX1, NHE1, SGK1, PKCβII, brain microvascular endothelial cells, ischemic stroke, cerebral edema, astrocyte swelling, middle cerebral artery occlusion, bumetanide, kinase phosphorylation
MeSH terms
Sodium-Hydrogen Exchanger 1, Serum-Glucocorticoid Regulated Kinases, Animals, Blood-Brain Barrier, Cattle, Cells, Cultured, Enzyme Activation, Glucose, Humans, Phosphorylation, Time Factors, Signal Transduction, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Sodium-Potassium-Chloride Symporters, Endothelial Cells, Protein Kinase C beta

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