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Am J Physiol Renal Physiol 286: F100-F110, 2004. First published September 23, 2003; doi:10.1152/ajprenal.00182.2003
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Troglitazone acts by PPAR{gamma} and PPAR{gamma}-independent pathways on LLC-PK1-F+ acid-base metabolism

Tomas Welbourne,1 Ellen Friday,2 Rocky Fowler,2 Francesco Turturro,2 and Itzhak Nissim3

Departments of 1Molecular and Cellular Physiology and 2Medicine and Feist-Weiller Cancer Center, Louisiana State University Health Science Center, Shreveport, Louisiana 71130; and 3Division of Child Development and Rehabilitation, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Submitted 9 May 2003 ; accepted in final form 12 September 2003

Troglitazone was studied in pH-sensitive LLC-PK1-F+ cells to determine the effect on pHi and glutamine metabolism as well as the role of peroxisome proliferator-activated receptor (PPAR{gamma})-dependent and PPAR{gamma}-independent signaling pathways. Troglitazone induces a dose-dependent cellular acidosis that occurs within 4 min and persists over 18 h as a result of inhibiting Na+/H+ exchanger-mediated acid extrusion. Cellular acidosis was associated with glutamine-dependent augmented [15N]ammonium production and decreased [15N]alanine formation from 15N-labeled glutamine. The shift in glutamine metabolism from alanine to ammoniagenesis appears within 3 h and is associated after 18 h with both a reduction in assayable alanine aminotransferase (ALT) activity as well as cellular acidosis. The relative contribution of troglitazone-induced cellular acidosis vs. the decrease in assayable ALT activity to alanine production could be demonstrated. The PPAR{gamma} antagonist bisphenol A diglycide ether (BADGE) reversed both the troglitazone-induced cellular acidosis and ammoniagenesis but enhanced the troglitazone reduction of assayable ALT activity; BADGE also blocked troglitazone induction of peroxisome proliferator response element-driven firefly luciferase activity. The protein kinase C (PKC) inhibitor chelerythrine mimics troglitazone effects, whereas phorbol ester reverses the effects on ammoniagenesis consistent with troglitazone negatively regulating the DAG/PKC/ERK pathway. Although functional PPAR{gamma} signaling occurs in this cell line, the major troglitazone-induced acid-base responses appear to be mediated by pathway(s) involving PKC/ERK.

intracellular pH; Na+/H+ exchanger; 15N-labeled glutamine; alanine aminotransferase activity; protein kinase C/extracellular regulated kinase


Address for reprint requests and other correspondence: T. Welbourne, Dept. of Molecular and Cellular Physiology, LSUHSC, Shreveport, LA 71130 (E-mail: twelbo{at}lsuhsc.edu).




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