A concerted role of Na+-K+-Cl- cotransporter and Na+/Ca2+ exchanger in ischemic damage

Jing Luo, Yanping Wang, Hai Chen, Douglas B. Kintner, Sam W. Cramer, Josiah K. Gerdts, Xinzhi Chen, Gary E. Shull, Kenneth D. Philipson, Dandan Sun

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Na+-K+-Cl- cotransporter isoform 1 (NKCC1) and Na+/Ca2+ exchanger isoform 1 (NCX1) were expressed in cortical neurons. Three hours of oxygen and glucose deprivation (OGD) significantly increased expression of full-length NCX1 protein (∼116 kDa), which remained elevated during 1 to 21 h reoxygenation (REOX) and was accompanied with concurrent cleavage of NCX1. Na+/Ca2+ exchanger isoform 1 heterozygous (NCX1+/-) neurons with ∼50% less of NCX1 protein exhibited ∼64% reduction in NCX-mediated Ca2+ influx. Expression of NCX1 and NKCC1 proteins was reduced in double heterozygous (NCX1+/-/NKCC1+/-) neurons. NCX-mediated Ca2+ influx was nearly abolished in these neurons. Three-hour OGD and 21-h REOX caused ∼80% mortality rate in NCX1+/+ neurons and in NCX1 +/- neurons. In contrast, NKCC1+/- neurons exhibited ∼45% less cell death. The lowest mortality rate was found in NCX1 +/-/NKCC1+/- neurons (∼65% less neuronal death). The increased tolerance to ischemic damage was also observed in NCX1 +/-/NKCC1+/- brains after transient cerebral ischemia. NCX1+/-/NKCC1+/- mice had a significantly reduced infarct volume at 24 and 72 h reperfusion. In conclusion, these data suggest that NKCC1 in conjunction with NCX1 plays a role in reperfusion-induced brain injury after ischemia.

Original languageEnglish (US)
Pages (from-to)737-746
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume28
Issue number4
DOIs
StatePublished - Apr 2008

Keywords

  • Ca overload
  • Focal ischemia
  • Infarction
  • KB-R7943
  • Neuronal death

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