Troglitazone and pioglitazone interactions via PPAR-gamma-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 microM but not Tro at 1 microM. On the other hand, PPAR-gamma-independent P-ERK activation was observed with 5 microM Tro but not with Pio (5-20 microM). In addition, Pio (1-10 microM) increased metabolic acid production and activated AMP-activated protein kinase (AMPK) associated with decreased mitochondrial membrane potential, whereas Tro (1-20 microM) 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.
Turturro
Francesco
F
Dept. of Medicine, Feist-Weiller Cancer Center, Louisiana State University Health Science Center, Shreveport, LA 71130, USA.
Oliver
Robert
R
Friday
Ellen
E
Nissim
Itzhak
I
Welbourne
Tomas
T
D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000008:administration & dosage*; D004338:Drug Combinations; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007684:Kidney Tubules / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D045162:Thiazolidinediones / Q000008:administration & dosage*; D000077288:Troglitazone
D002839:Chromans; D004338:Drug Combinations; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077288:Troglitazone; D000077205:Pioglitazone