title: GW501516, a PPARδ agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFκB pathway in mice.
abstract: Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(-). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Keiji
authors.initials: K
authors.lastname: Isshiki
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Detian
authors.initials: D
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishio
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D015151:Immunoblotting; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011507:Proteinuria / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013844:Thiazoles / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D018932:Chemokine CCL2; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D047494:PPAR delta; D034741:RNA, Small Interfering; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C425931:GW 501516