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independent and dependent pathways in regulating physiological responses in renal tubule derived cell lines
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
and PPAR-independent pathways was studied in cell lines derived from porcine renal tubules. PPAR-dependent activation of PPRE-driven luciferase gene expression was observed with Pio at 1uM but not Tro at 1µM. On the other hand PPAR-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 dependent and two PPAR-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 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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