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Am J Physiol Cell Physiol (October 25, 2006). doi:10.1152/ajpcell.00396.2006
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Submitted on July 21, 2006
Accepted on October 13, 2006

Troglitazone and Pioglitazone interactions via PPAR{gamma} independent and dependent pathways in regulating physiological responses in renal tubule derived cell lines

Francesco Turturro1, Robert E Oliver III2, Ellen Friday1, Itzhak Nissim3, and Tomas C. Welbourne4*

1 1Department of Medicine, Feist-Weiller Cancer Center and 2 Gene Therapy Program, Louisiana State University Health Science Center, Shreveport, Louisiana, United States
2 Departments of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana, United States
3 Department of Pediatrics, University of Pennsylvania, Philadephia, Pennsylvania, United States
4 Department of Physiol. & Biophysics, LSU Med Center, Shreveport, Louisiana, United States

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

Troglitazone and Pioglitazone activation of PPAR{gamma} and PPAR{gamma}-independent pathways was studied in cell lines derived from porcine renal tubules. PPAR{gamma}-dependent activation of PPRE-driven luciferase gene expression was observed with Pio at 1uM but not Tro at 1µM. On the other hand PPAR{gamma}-independent P-ERK activation was observed with 5µM Tro but not with Pio (5-20µM). In addition Pio (1-10µM) increased metabolic acid production and activated AMPK associated with decreased mitochondrial membrane potential whereas Tro (1-20µM) did not. These results are consistent with one PPAR{gamma} dependent and two PPAR{gamma}-independent pathways through which glitazones may act in effecting metabolic processes (ammoniagenesis and gluconeogenesis) as well as cellular growth: 1) PPRE-driven gene expression, 2) P-ERK activation and 3) mitochondrial-AMPK activation. The pathways influence cellular acidosis and glucose and glutamine metabolism in a manner favoring reduced plasma glucose in vivo. In addition, significant interactions can be demonstrated which enhances some physiological processes (ammonigenesis) and suppresses others (ligand-mediated PPAR{gamma} gene expression). Our findings provide a model for both understanding seemingly opposite biological effects as well as for enhancing therapeutic potency of these agents.




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