Perfluorooctanesulfonate Mediates Renal Tubular Cell Apoptosis through PPARgamma Inactivation

PLoS One. 2016 May 12;11(5):e0155190. doi: 10.1371/journal.pone.0155190. eCollection 2016.

Abstract

Perfluorinated chemicals (PFCs) are ubiquitously distributed in the environments including stainless pan-coating, raincoat, fire extinguisher, and semiconductor products. The PPAR family has been shown to contribute to the toxic effects of PFCs in thymus, immune and excretory systems. Herein, we demonstrated that perfluorooctanesulfonate (PFOS) caused cell apoptosis through increasing ratio of Bcl-xS/xL, cytosolic cytochrome C, and caspase 3 activation in renal tubular cells (RTCs). In addition, PFOS increased transcription of inflammatory cytokines (i.e., TNFα, ICAM1, and MCP1) by NFκB activation. Conversely, PFOS reduced the mRNA levels of antioxidative enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, as a result of reduced PPARγ transactivational activity by using reporter and chromatin immuoprecipitation (ChIP) assays. PFOS reduced the protein interaction between PPARγ and PPARγ coactivator-1 alpha (PGC1α) by PPARγ deacetylation through Sirt1 upregulation, of which the binding of PPARγ and PGC1α to a peroxisome proliferator response element (PPRE) in the promoter regions of these antioxidative enzymes was alleviated in the ChIP assay. Furthermore, Sirt1 also deacetylated p53 and then increased the binding of p53 to Bax, resulting in increased cytosolic cytochrome C. The effect of PPARγ inactivation by PFOS was validated using the PPARγ antagonist GW9662, whereas the adverse effects of PFOS were prevented by PPARγ overexpression and activators, rosiglitozone and L-carnitine, in RTCs. The in vitro finding of protective effect of L-carnitine was substantiated in vivo using Balb/c mice model subjected to PFOS challenge. Altogether, we provide in vivo and in vitro evidence for the protective mechanism of L-carnitine in eliminating PFOS-mediated renal injury, at least partially, through PPARγ activation.

MeSH terms

  • Acetylation / drug effects
  • Alkanesulfonic Acids / toxicity*
  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects*
  • Carnitine / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • Cytochromes c / metabolism
  • Cytosol / metabolism
  • Fluorocarbons / toxicity*
  • Genes, Reporter
  • Inflammation / pathology
  • Kidney Function Tests
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology*
  • Kidney Tubules / physiopathology
  • Male
  • Mice, Inbred BALB C
  • Oxidation-Reduction / drug effects
  • PPAR gamma / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Protective Agents / pharmacology
  • Protein Binding / drug effects
  • Rats
  • Response Elements / genetics
  • Rosiglitazone
  • Signal Transduction / drug effects
  • Sirtuin 1 / metabolism
  • Thiazolidinediones / pharmacology
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-2-Associated X Protein / metabolism

Substances

  • Alkanesulfonic Acids
  • Antioxidants
  • Fluorocarbons
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protective Agents
  • Thiazolidinediones
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • Rosiglitazone
  • Cytochromes c
  • perfluorooctane sulfonic acid
  • Sirtuin 1
  • Carnitine

Grant support

This study was supported by grants from Ministry of Science and Technology of Taiwan; www.most.gov.tw (MOST103-2314-B-585-002; NSC102-2320-B-038-030-MY3) and En-Chu-Kong Hospital; www.eck.org.tw/index.aspx?siteid=218&ver=admi (a regional hospital in the Taipei County; ECKH 10303; ECKH10304). Additionally, authors Li-Li Wen and Chien-Yu Lin receive salaries from En-Chu-Kong Hospital. However, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.