Differential effects of peroxisome proliferator activated receptor-γ (PPARγ) ligands in proximal tubular cells: Thiazolidinediones are partial PPARγ agonists

Abstract

Background. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with multiple effects on target cell function. PPARγ activity is regulated by extracellular signal-regulated protein kinase (ERK), mitogen-activated protein (MAP) kinase, and PPARγ ligands have varying effects on activity of ERK. Different PPARγ 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 PPARγ, 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 PPARγ 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 PPARα agonists, and only very modestly stimulated by a PPARβ agonist The PPARγ agonists 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ 2), ciglitazone, and troglitazone stimulated significant transcriptional activation and phosphorylation of PPARγ. These effects were more marked with 15d-PGJ2. Thiazolidinediones attenuated 15d-PGJ2 evoked PPARγ activation and phosphorylation. ERK activity positively regulated PPAR activation. Only 15d-PGJ2 stimulated ERK activity and cell proliferation, and these effects were also inhibited by thiazolidinediones. Conclusion. PPARγ agonists exert differential effects in proximal tubule cells with thiazolidinediones behaving as partial agonists.