Peroxisome proliferator-activated receptor (PPAR) agonists protect human podocytes against cell death induced by oxygen/glucose deprivation-reoxygenation

PPAR are ligand-activated transcription factors and three subtypes (α, β/δ and γ) have been identified. PPAR agonists have been shown to decrease glomerular injury in in vivo models of renal ischema/reperfusion (I/R) [1,2]. However, whether a direct effect on cellular components of the glomerular filtration barrier contributes to the observed protection remains to be established. By using oxygen/glucose deprivation (OGD)-reoxygenation as an in vitro model that mimics in vivo I/R, the effects of selective PPAR agonists on podocyte death have been compared. Human immortalized podocytes have been pre-treated with gemfibrozil (PPARα), PPARGW0742 (PPARβ/δ), pioglitazone or rosiglitazone (PPARγ), either as acute (single dose) or repeated (3 days exposure) challenge. Cell death was measured as decrease in cell number, necrosis and apoptosis. Only the repeated pre-treatment with each agonist significantly prevented cell death, mainly by decreasing apoptosis. In comparison, in a model of serum-deprivation (48 h)-induced apoptosis both pre-treatments were effective, although the repeated one achieving the highest maximal effects. These results suggest that PPAR agonists protect podocytes mainly by decreasing apoptotic cell death. These findings contribute to clarify the pathophysiological role of PPARs in the kidney and indicate them as pharmacological targets for I/R-induced glomerular diseases. 1. Portilla D. et al., (2000). Etomoxir-induced PPAR-modulated enzymes protect during acute renal failure. Am J Physiol Renal Physiol. 278: F667-F675. 2. Collino M, et al., (2005). The selective PPAR antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion. Kidney Int 68: 529-536.