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Am J Physiol Cell Physiol (March 10, 2004). doi:10.1152/ajpcell.00560.2003
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Submitted on December 10, 2003
Accepted on March 4, 2004

Increased Tolerance to Oxygen and Glucose Deprivation in Astrocytes from Na+/H+ Exchanger Isoform 1 Null Mice

Douglas B Kintner1, Gui Su2, Brent J Lenart1, Andy J Ballard1, Jamie W Meyer3, Leong L Ng4, Gary E Shull3, and Dandan Sun2*

1 Department of Neurosurgery, University of Wisconsin- Madison, Madison, WI, USA
2 Department of Neurosurgery, University of Wisconsin- Madison, Madison, WI, USA; Department of Physiology, University of Wisconsin-Madison, Madsion, WI, USA
3 Department of Molecular Genetics Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH, USA
4 Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom

* To whom correspondence should be addressed. E-mail: sun{at}neurosurg.wisc.edu.

The ubiquitously expressed Na/H exchanger isoform 1 (NHE1) functions as a major intracellular pH (pHi) regulatory mechanism in many cell types, and in some tissues its activity may contribute to ischemic injury. In the present study, cortical astrocyte cultures from wild type (NHE1+/+) and NHE1-deficient (NHE1-/-) mice were used to investigate the role of NHE1 in pHi recovery and ischemic injury in astrocytes. In the absence of HCO3-, the mean resting pHi levels were 6.86 ± 0.03 in NHE1+/+ astrocytes and 6.53 ± 0.04 in NHE1-/- astrocytes. Removal of extracellular Na+ or blocking of NHE1 activity by the potent NHE1 inhibitor HOE-642 significantly reduced the resting level of pHi in NHE1+/+ astrocytes. NHE1+/+ astrocytes exhibited a rapid pHi recovery (0.33 ± 0.08 pH unit/min) following NH4Cl pre-pulse acid load. The pHi recovery in NHE1+/+ astrocytes was reversibly inhibited by HOE-642 or removal of extracellular Na+. In NHE1-/- astrocytes, the pHi recovery following acidification was impaired and not affected by either Na+-free conditions or HOE-642. Furthermore, 2 h oxygen and glucose deprivation (OGD) led to ~80% increase in pHi recovery rate in NHE1+/+ astrocytes. OGD induced a 5-fold rise in [Na+]i and 26% swelling in NHE1+/+ astrocytes. HOE-642 or genetic ablation of NHE1 significantly reduced the Na+ rise and swelling following OGD. These results suggest that NHE1 is the major pHi regulatory mechanism in cortical astrocytes and that ablation of NHE1 in astrocytes attenuates ischemia-induced disruption of ionic regulation and swelling.




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