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Effects of NHE1 expression level on CHO cell responses to environmental stress

Lisa R Abston1, William M Miller

  • 1Interdepartmental Biological Sciences Program, Northwestern University, Evanston, Illinois 60208, USA.

Biotechnology Progress
|April 2, 2005
PubMed

Insights

Overexpressing the Na+/H+ exchanger 1 (NHE1) protects Chinese hamster ovary (CHO) cells from lactic acid and ammonia. However, NHE1 levels did not impact cell growth inhibition from elevated carbon dioxide (CO2) or osmolality.

Area of Science:

  • Cell biology
  • Biochemistry
  • Physiology

Background:

  • Metabolic byproducts like ammonia, lactate, and CO2 inhibit animal cell growth and decrease intracellular pH (pH(i)).
  • Eukaryotic cells utilize transport systems to regulate pH(i), but the protective role of specific ion transporters against these metabolic byproducts has not been fully explored.
  • Na+/H+ exchangers (NHE) are key in extruding H+ ions to maintain intracellular pH.

Purpose of the Study:

  • To investigate whether overexpression of NHE1 provides Chinese hamster ovary (CHO) cells with enhanced protection against elevated levels of ammonia, lactate, or CO2.
  • To compare the survival and growth of CHO cells with normal, overexpressed, or absent NHE1 activity under various stress conditions.

Main Methods:

  • Generated and utilized three distinct CHO cell lines: one overexpressing NHE1, one with normal NHE1 levels (MT2-1-8), and one lacking NHE1 activity (AP-1).
  • Exposed these cell lines to varying concentrations of lactic acid, ammonia, and CO2, alongside different osmolality conditions.
  • Assessed cell survival and growth rates to determine the impact of NHE1 expression levels under these metabolic challenges.

Main Results:

  • Expression of at least normal levels of NHE1 is crucial for CHO cell survival when exposed to 30 mM lactic acid or 20 mM NH4Cl.
  • Overexpression of NHE1 significantly increased resistance to acute acid-loads.
  • Elevated carbon dioxide (pCO2) and osmolality (up to 195 mmHg pCO2/435 mOsm/kg) did not affect cell growth inhibition regardless of NHE1 levels.
  • Absence of NHE1 expression did not lead to further decreases in cell growth under elevated osmolality alone (up to 575 mOsm/kg).

Conclusions:

  • NHE1 plays a vital role in protecting CHO cells against acid stress induced by lactic acid and ammonia.
  • The protective mechanism of NHE1 is specific and does not extend to mitigating growth inhibition caused by high levels of CO2 or osmotic stress.
  • Maintaining adequate NHE1 function is essential for cellular homeostasis under certain metabolic challenges.

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