Differential effects of peroxisome proliferator activated receptor-gamma (PPAR gamma) ligands in proximal tubular cells: thiazolidinediones are partial PPAR gamma agonists.
Background. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with multiple effects on target cell function. PPAR gamma activity is regulated by extracellular signal-regulated protein kinase (ERK), mitogen-activated protein (MAP) kinase, and PPAR gamma ligands have varying effects on activity of ERK. Different PPAR gamma ligands have been shown to have both protective and detrimental effects in the kidney. Since transcriptional activation by different PPAR agonists is ligand- and depot-specific PPAR gamma, we have examined the effects of different agonists on PPAR activity in the proximal tubule.


METHODS
Opossum kidney cells were used in all experiments, transiently transfected with a PPAR response element luciferase reporter and subject to stimulation with various PPAR ligands. The role of ERK and phosphorylation in PPAR gamma activation were studied, as were the effects of PPAR agonists on ERK activation and cell proliferation.


RESULTS
Transcriptional activity of PPAR was not stimulated by PPAR alpha agonists, and only very modestly stimulated by a PPAR beta agonist. The PPAR gamma agonists 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), ciglitazone, and troglitazone stimulated significant transcriptional activation and phosphorylation of PPAR gamma. These effects were more marked with 15d-PGJ(2). Thiazolidinediones attenuated 15d-PGJ(2) evoked PPAR gamma activation and phosphorylation. ERK activity positively regulated PPAR activation. Only 15d-PGJ(2) stimulated ERK activity and cell proliferation, and these effects were also inhibited by thiazolidinediones.


CONCLUSIONS
PPAR gamma agonists exert differential effects in proximal tubule cells with thiazolidinediones behaving as partial agonists.
Chana
Ravinder S
RS
Department of Cell Physiology and Pharmacology, University of Leicester, Faculty of Medicine and Biological Sciences, Leicester, England, United Kingdom.
Lewington
Andrew J
AJ
Brunskill
Nigel J
NJ
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D008024:Ligands; D009893:Opossums; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D000077288:Troglitazone
C477819:15-deoxyprostaglandin J2; D002839:Chromans; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D048049:Extracellular Signal-Regulated MAP Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2; C039671:ciglitazone