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

Troglitazone (Tro) and pioglitazone (Pio) activation of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-gamma-independent pathways was studied in cell lines derived from porcine renal tubules. PPAR-gamma-dependent activation of PPAR response element-driven luciferase gene expression was observed with Pio at 1 mu M but not Tro at 1 mu M. On the other hand, PPAR-gamma-independent P-ERK activation was observed with 5 mu M Tro but not with Pio (5-20 mu M). In addition, Pio (1-10 mu M) increased metabolic acid production and activated AMP-activated protein kinase (AMPK) associated with decreased mitochondrial membrane potential, whereas Tro (1-20 mu M) 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-gamma-dependent and PPAR-gamma-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-gamma gene expression). Our findings provide a model both for understanding seemingly opposite biological effects and for enhancing therapeutic potency of these agents.