title: Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice.
abstract: OBJECTIVE
  Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-δ has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPARδ is atheroprotective; however, the role of PPARδ in renal function remains unclear. Here, we report the renoprotective effects of PPARδ activation in a model of streptozotocin-induced diabetic nephropathy.
  
  
  METHODS
  Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and 3) diabetic mice treated with the PPARδ agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes.
  
  
  RESULTS
  GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPARδ activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression.
  
  
  CONCLUSIONS
  These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPARδ agonists and support the concept that PPARδ agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Chikage
authors.initials: C
authors.lastname: Sato
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tachibana
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyota
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D018932:Chemokine CCL2; D053495:Osteopontin; D047494:PPAR delta; D051560:Proto-Oncogene Proteins c-bcl-6; D013844:Thiazoles; 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