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Am J Physiol Regul Integr Comp Physiol (January 24, 2002). doi:10.1152/ajpregu.00506.2001
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Articles in PresS, published online ahead of print January 24, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00506.2001
Submitted on August 17, 2001
Accepted on January 19, 2002

Troglitazone Induces a Cellular Acidosis by Inhibiting Acid Extrusion in Cultured Rat Mesangial Cells

Tomas C Welbourne*, Gan Su, Gregory A Coates, Robert E Routh, Kevin J McCarthy, and Harold D Battarbee

* To whom correspondence should be addressed. E-mail: twelbo{at}lsumc.edu.

We studied the effect of troglitazone on cellular acid-base balance and alanine formation in isolated rat mesangial cells. Mesangial cells were grown to confluency in RPMI 1640 media on 30mm chambers used to monitor both cellular pH using the pH-sensitive dye 2'7'-bis (2-carboxyethyl)-5,6-carboxyfluorescein and metabolic acid production as well as glutamine metabolism. Troglitazone (10µM) induced a spontaneous cellular acidosis (6.95±0.02 vs. 7.47±0.04 respectively, p<0.0001) but without an increase in lactic acid production. Alanine production was reduced 64% (p<0.01) consistent with inhibition of the glutamate transamination. These findings pointed to a decrease in acid extrusion rather than an increase in acid production as the underlying mechanism leading to the cellular acidosis. To test their acid extrusion capabilities mesangial cells were acid loaded with NH4+ and then allowed to recover in Krebs-Henseleit media or in Krebs-Henseleit media minus bicarbonate (HEPES substituted) and the recovery response ({Delta}pHi/min) monitored. In the presence of 10µM troglitazone the recovery response to the NH4+ acid load was virtually eliminated in the bicarbonate buffered media (0.0±0.001 vs. 0.06±0.02 pHi/min, p<0.0001 vs. control) and reduced more than 63% in HEPES buffered media (0.01±0.01 pHi/min, p<0.002 vs. control). These results show that troglitazone induces a cellular acidosis resulting from a reduction in cellular acid extrusion.




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