title: Protective effects of peroxisome proliferator-activated receptor agonists on human podocytes: proposed mechanisms of action.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor (PPAR) agonists exert anti-albuminuric effects. However, the nephroprotective effects of these drugs remain to be fully understood. We have investigated whether gemfibrozil, GW0742 and pioglitazone protect human podocytes against nutrient deprivation (ND)-induced cell death and the role of mitochondrial biogenesis as a cytoprotective process.
  
  
  METHODS
  Immortalized human podocytes were pre-treated with the PPAR agonists and exposed to ND (5 h) under normoxia, hypoxia or in the presence of pyruvate. Cell death was measured at the end of the ND and of the recovery phase (24 h). Mitochondrial mass, cytochrome c oxidase (COX) subunits 1 and 4 were measured as markers of mitochondrial cell content, while membrane potential as an index of mitochondrial function. PGC-1α, NRF1 and Tfam expression was studied, as crucial regulators of mitochondrial biogenesis.
  
  
  RESULTS
  Cell pre-treatment with gemfibrozil, GW0742, or pioglitazone significantly decreased the ND-induced cell loss, necrosis and apoptosis. These effects were attenuated by hypoxia and potentiated by pyruvate. Pre-treatment with these drugs significantly increased mitochondrial cell content, while it did not affect mitochondrial function. In all these experiments pioglitazone exerted significantly larger effects than gemfibrozil or GW0742.
  
  
  CONCLUSIONS
  Gemfibrozil, GW0742 and pioglitazone may exert direct protective effects on human podocytes. Mitochondrial biogenesis is a cell response to the PPAR agonists related to their cytoprotective activity. These results provide a mechanistic support to the clinical evidence indicating PPAR agonists as disease-modifying agents for glomerular diseases.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy. gianluca.miglio@unito.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.forename: Arianna Carolina
authors.initials: AC
authors.lastname: Rosa
authors.forename: Lorenza
authors.initials: L
authors.lastname: Rattazzi
authors.forename: Cristina
authors.initials: C
authors.lastname: Grange
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D063269:Mitochondrial Turnover / Q000187:drug effects*; D009336:Necrosis / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D000077205:Pioglitazone; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D003576:Electron Transport Complex IV; D015248:Gemfibrozil; D047492:Peroxisome Proliferator-Activated Receptors; D000077205:Pioglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds