The PPARβ/δ Agonist GW501516 Attenuates Peritonitis in Peritoneal Fibrosis via Inhibition of TAK1–NFκB Pathway in Rats

Abstract

Peritoneal fibrosis is a common consequence of long-term peritoneal dialysis (PD), and peritonitis is a factor in its onset. Agonist-bound peroxisome proliferator-activated receptors (PPARs) function as key regulators of energy metabolism and inflammation. Here, we examined the effects of PPARβ/δ agonist GW501516 on peritonitis in a rat peritoneal fibrosis model. Peritoneal fibrosis secondary to inflammation was induced into uremic rats by daily injection of Dianeal 4.25 % PD solutions along with six doses of lipopolysaccharide before commencement of GW501516 treatment. Normal non-uremic rats served as control, and all rats were fed with a control diet or a GW501516-containing diet. Compared to control group, exposure to PD fluids caused peritoneal fibrosis that was accompanied by increased mRNA levels of monocyte chemoattractant protein-1, tumor necrotic factor-α, and interleukin-6 in the uremic rats, and these effects were prevented by GW501516 treatment. Moreover, GW501516 was found to attenuate glucose-stimulated inflammation in cultured rat peritoneal mesothelial cells via inhibition of transforming growth factor-β-activated kinase 1 (TAK1), and nuclear factor kappa B (NFκB) signaling pathway (TAK1–NFκB pathway), a main inflammation regulatory pathway. In conclusion, inhibition of TAK1–NFκB pathway with GW501516 may represent a novel therapeutic approach to ameliorate peritonitis-induced peritoneal fibrosis for patients on PD.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Levey, A.S., R. Atkins, J. Coresh, E.P. Cohen, A.J. Collins, K.U. Eckardt, M.E. Nahas, B.L. Jaber, M. Jadoul, A. Levin, N.R. Powe, J. Rossert, D.C. Wheeler, N. Lameire, and G. Eknoyan. 2007. Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney International 72: 247–259.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Weiner, D.E. 2007. Causes and consequences of chronic kidney disease: implications for managed health care. Journal Of Managed Care Pharmacy 13: S1–S9.

    PubMed  Google Scholar 

  3. 3.

    Kramann, R., J. Floege, M. Ketteler, N. Marx, and V.M. Brandenburg. 2012. Medical options to fight mortality in end-stage renal disease: a review of the literature. Nephrology Dialysis Transplantation 27: 4298–4307.

    CAS  Article  Google Scholar 

  4. 4.

    Margetts, P.J., and P. Bonniaud. 2003. Basic mechanisms and clinical implications of peritoneal fibrosis. Peritoneal Dialysis International 23: 530–541.

    CAS  PubMed  Google Scholar 

  5. 5.

    Chow, F.Y., D.J. Nikolic-Paterson, E. Ozols, R.C. Atkins, B.J. Rollin, and G.H. Tesch. 2006. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney International 69: 73–80.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Shim, J., H.O. Byun, Y.D. Lee, E.S. Lee, and S. Sohn. 2009. Interleukin-6 small interfering RNA improved the herpes simplex virus-induced systemic inflammation in vivo Behcet’s disease-like mouse model. Gene Therapy 16: 415–425.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Krediet, R.T., and D.G. Struijk. 2013. Peritoneal changes in patients on long-term peritoneal dialysis. Nature Reviews Nephrology 9: 419–429.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Williams, J.D., K.J. Craig, N. Topley, C. Von Ruhland, M. Fallon, G.R. Newman, R.K. Mackenzie, and G.T. Williams. 2002. Morphologic changes in the peritoneal membrane of patients with renal disease. Journal of the American Society of Nephrology 13: 470–479.

    PubMed  Google Scholar 

  9. 9.

    Williams, J.D., K.J. Craig, N. Topley, and G.T. Williams. 2003. Peritoneal dialysis: changes to the structure of the peritoneal membrane and potential for biocompatible solutions. Kidney International 84: S158–161.

    PubMed  Article  Google Scholar 

  10. 10.

    Brown, J.D., and J. Plutzky. 2007. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation 115: 518–533.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Guan, Y., and M.D. Breyer. 2001. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease. Kidney International 60: 14–30.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Gervois, P., J.C. Fruchart, and B. Staels. 2007. Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nature Clinical Practice Endocrinology & Metabolism 3: 145–156.

    CAS  Article  Google Scholar 

  13. 13.

    Wang, Y.X., C.H. Lee, S. Tiep, R.T. Yu, J. Ham, H. Kang, and R.M. Evans. 2003. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113: 159–170.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Barish, G.D., A.R. Atkins, M. Downes, P. Olson, L.W. Chong, M. Nelson, Y. Zou, H. Hwang, H. Kang, L. Curtiss, R.M. Evans, and C.H. Lee. 2008. PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America 105: 4271–4276.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  15. 15.

    Takata, Y., J. Liu, F. Yin, A.R. Collins, C.J. Lyon, C.H. Lee, A.R. Atkins, M. Downes, G.D. Barish, R.M. Evans, W.A. Hsueh, and R.K. Tangirala. 2008. PPAR delta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America 105: 4277–4282.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. 16.

    Yang, X., S. Kume, Y. Tanaka, K. Isshiki, S. Araki, M. Chin-Kanasaki, T. Sugimoto, D. Koya, M. Haneda, T. Sugaya, D. Li, P. Han, Y. Nishio, A. Kashiwagi, H. Maegawa, and T. Uzu. 2011. GW501516, a PPARdelta agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFkappaB pathway in mice. PLoS One 6: e25271.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  17. 17.

    Piqueras, L., M.J. Sanz, M. Perretti, E. Morcillo, L. Norling, J.A. Mitchell, Y. Li, and D. Bishop-Bailey. 2009. Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release. Journal of Leukocyte Biology 86: 115–122.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Oliver Jr., W.R., J.L. Shenk, M.R. Snaith, C.S. Russell, K.D. Plunket, N.L. Bodkin, M.C. Lewis, D.A. Winegar, M.L. Sznaidman, M.H. Lambert, H.E. Xu, D.D. Sternbach, S.A. Kliewer, B.C. Hansen, and T.M. Willson. 2001. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proceedings of the National Academy of Sciences of the United States of America 98: 5306–5311.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  19. 19.

    Margetts, P.J., and P. Bonniaud. 2003. Basic mechanisms and clinical implications of peritoneal fibrosis. Peritoneal Dialysis International 23: 530–541.

    CAS  PubMed  Google Scholar 

  20. 20.

    Guo, H., J.C. Leung, M.F. Lam, L.Y. Chan, A.W. Tsang, H.Y. Lan, and K.N. Lai. 2007. Smad7 transgene attenuates peritoneal fibrosis in uremic rats treated with peritoneal dialysis. Journal of the American Society of Nephrology 18: 2689–2703.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Song, S.H., I.S. Kwak, B.Y. Yang, D.W. Lee, S.B. Lee, and M.Y. Lee. 2009. Role of rosiglitazone in lipopolysaccharide-induced peritonitis: a rat peritoneal dialysis model. Nephrology (Carlton, Vic.) 14: 155–163.

    CAS  Article  Google Scholar 

  22. 22.

    Schaller, E., A.J. Macfarlane, R.A. Rupec, S. Gordon, A.J. McKnight, and K. Pfeffer. 2002. Inactivation of the F4/80 glycoprotein in the mouse germ line. Molecular and Cellular Biology 22: 8035–8043.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  23. 23.

    Bot, J., D. Whitaker, J. Vivian, R. Lake, V. Yao, and R. McCauley. 2003. Culturing mouse peritoneal mesothelial cells. Pathology Research and Practice 199: 341–344.

    Article  Google Scholar 

  24. 24.

    Muller, P.Y., H. Janovjak, A.R. Miserez, and Z. Dobbie. 2002. Processing of gene expression data generated by quantitative real-time RT-PCR. Biotechniques 32: 1372–1374. 1376, 1378–1379.

    CAS  PubMed  Google Scholar 

  25. 25.

    Talkington, D.F. 2013. Real-time PCR in food science: current technology and applications. Emerging Infectious Diseases 19: 1352–1353.

    PubMed Central  Article  Google Scholar 

  26. 26.

    Worrad, D.M., B.M. Turner, and R.M. Schultz. 1995. Temporally restricted spatial localization of acetylated isoforms of histone H4 and RNA polymerase II in the 2-cell mouse embryo. Development 121: 2949–2959.

    CAS  PubMed  Google Scholar 

  27. 27.

    Kaneko, K., C. Hamada, and Y. Tomino. 2007. Peritoneal fibrosis intervention. Peritoneal Dialysis International 27: S82–S86.

    PubMed  Google Scholar 

  28. 28.

    Pletinck, A., R. Vanholder, N. Veys, and W. Van Biesen. 2012. Protecting the peritoneal membrane: factors beyond peritoneal dialysis solutions. Nature Reviews Nephrology 8: 542–550.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Tamura, M., A. Osajima, S. Nakayamada, H. Anai, N. Kabashima, K. Kanegae, T. Ota, Y. Tanaka, and Y. Nakashima. 2003. High glucose levels inhibit focal adhesion kinase-mediated wound healing of rat peritoneal mesothelial cells. Kidney International 63: 722–731.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Ghosh, S., and M. Karin. 2002. Missing pieces in the NF-kappaB puzzle. Cell 109: S81–S96.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Fan, Y.H., Y. Yu, R.F. Mao, X.J. Tan, G.F. Xu, H. Zhang, X.B. Lu, S.B. Fu, and J. Yang. 2011. USP4 targets TAK1 to downregulate TNFalpha-induced NF-kappaB activation. Cell Death and Differentiation 18: 1547–1560.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. 32.

    Neri, T., C. Armani, A. Pegoli, C. Cordazzo, Y. Carmazzi, S. Brunelleschi, C. Bardelli, M.C. Breschi, P. Paggiaro, and A. Celi. 2011. Role of NF-kappaB and PPAR-gamma in lung inflammation induced by monocyte-derived microparticles. European Respiratory Journal 37: 1494–1502.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Kostadinova, R., A. Montagner, E. Gouranton, S. Fleury, H. Guillou, D. Dombrowicz, P. Desreumaux, and W. Wahli. 2012. GW501516-activated PPARbeta/delta promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Bioscience 2: 34.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  34. 34.

    Wenzel, U., A. Schneider, A.J. Valente, H.E. Abboud, F. Thaiss, U.M. Helmchen, and R.A. Stahl. 1997. Monocyte chemoattractant protein-1 mediates monocyte/macrophage influx in anti-thymocyte antibody-induced glomerulonephritis. Kidney International 51: 770–776.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Stenvinkel, P., M. Ketteler, R.J. Johnson, B. Lindholm, R. Pecoits-Filho, M. Riella, O. Heimburger, T. Cederholm, and M. Girndt. 2005. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia—the good, the bad, and the ugly. Kidney International 67: 1216–1233.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Biswas, S.K., and A. Sodhi. 2002. In vitro activation of murine peritoneal macrophages by monocyte chemoattractant protein-1: upregulation of CD11b, production of proinflammatory cytokines, and the signal transduction pathway. Journal of Interferon & Cytokine Research 22: 527–538.

    CAS  Article  Google Scholar 

  37. 37.

    Ferreira, A.M., S. Takagawa, R. Fresco, X. Zhu, J. Varga, and L.A. DiPietro. 2006. Diminished induction of skin fibrosis in mice with MCP-1 deficiency. Journal of Investigative Dermatology 126: 1900–1908.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Kassel, K.M., G.L. Guo, O. Tawfik, and J.P. Luyendyk. 2010. Monocyte chemoattractant protein-1 deficiency does not affect steatosis or inflammation in livers of mice fed a methionine-choline-deficient diet. Laboratory Investigation 90: 1794–1804.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. 39.

    Westergaard, M., J. Henningsen, C. Johansen, S. Rasmussen, M.L. Svendsen, U.B. Jensen, H.D. Schroder, B. Staels, L. Iversen, L. Bolund, K. Kragballe, and K. Kristiansen. 2003. Expression and localization of peroxisome proliferator-activated receptors and nuclear factor kappaB in normal and lesional psoriatic skin. Journal of Investigative Dermatology 121: 1104–1117.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Coll, T., D. Alvarez-Guardia, E. Barroso, A.M. Gomez-Foix, X. Palomer, J.C. Laguna, and M. Vazquez-Carrera. 2010. Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells. Endocrinology 151: 1560–1569.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Barroso, E., E. Eyre, X. Palomer, and M. Vazquez-Carrera. 2011. The peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) agonist GW501516 prevents TNF-alpha-induced NF-kappaB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. Biochemical Pharmacology 81: 534–543.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Douvdevani, A., O. Abramson, A. Tamir, A. Konforty, N. Isakov, and C. Chaimovitz. 1995. Commercial dialysate inhibits TNF alpha mRNA expression and NF-kappa B DNA-binding activity in LPS-stimulated macrophages. Kidney International 47: 1537–1545.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Hayden, M.S., and S. Ghosh. 2011. NF-kappaB in immunobiology. Cell Research 21: 223–244.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  44. 44.

    Li, Q., and I.M. Verma. 2002. NF-kappaB regulation in the immune system. Nature Reviews Immunology 2: 725–734.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Ghosh, S., and M.S. Hayden. 2008. New regulators of NF-kappaB in inflammation. Nature Reviews Immunology 8: 837–848.

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Detian Li.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Su, X., Zhou, G., Wang, Y. et al. The PPARβ/δ Agonist GW501516 Attenuates Peritonitis in Peritoneal Fibrosis via Inhibition of TAK1–NFκB Pathway in Rats. Inflammation 37, 729–737 (2014). https://doi.org/10.1007/s10753-013-9791-z

Download citation

KEY WORDS

  • GW501516
  • PPARβ/δ
  • TAK1–NFκB pathway
  • peritonitis
  • peritoneal fibrosis