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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Troglitazone and pioglitazone interactions via PPAR--independent and -dependent pathways in regulating physiological responses in renal tubule-derived cell lines

¹Department of Medicine, Feist-Weiller Cancer Center, ²Gene Therapy Program, and ³Departments of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana; and ⁴Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 21 July 2006 ; accepted in final form 13 October 2006

Troglitazone (Tro) and pioglitazone (Pio) activation of peroxisome proliferator-activated receptor (PPAR)- and PPAR--independent pathways was studied in cell lines derived from porcine renal tubules. PPAR--dependent activation of PPAR response element-driven luciferase gene expression was observed with Pio at 1 µM but not Tro at 1 µM. On the other hand, PPAR--independent P-ERK activation was observed with 5 µM Tro but not with Pio (5–20 µM). In addition, Pio (1–10 µM) increased metabolic acid production and activated AMP-activated protein kinase (AMPK) associated with decreased mitochondrial membrane potential, whereas Tro (1–20 µM) did not. These results are consistent with three pathways through which glitazones may act in effecting metabolic processes (ammoniagenesis and gluconeogenesis) as well as cellular growth: 1) PPAR--dependent and PPAR--independent pathways, 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 that enhance some physiological processes (ammoniagenesis) and suppress others (ligand-mediated PPAR- gene expression). Our findings provide a model both for understanding seemingly opposite biological effects and for enhancing therapeutic potency of these agents.

peroxisome proliferator-activated receptor-; phospho-extracellular signal-regulated kinase; intracellular pH; Na⁺/H⁺ exchanger; AMP-activated protein kinase; mitochondria

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