title: Fenofibrate, a PPARα agonist, has renoprotective effects in mice by enhancing renal lipolysis.
abstract: As renal lipotoxicity can lead to chronic kidney disease (CKD), we examined the role of peroxisome proliferator-activated receptor (PPAR)-α, a positive regulator of renal lipolysis. Feeding mice a high-fat diet induced glomerular injury, and treating them with fenofibrate, a PPARα agonist, increased the expression of lipolytic enzymes and reduced lipid accumulation and oxidative stress in glomeruli, while inhibiting the development of albuminuria and glomerular fibrosis. In mice given an overload of free fatty acid-bound albumin to induce tubulointerstitial injury, fenofibrate attenuated the development of oxidative stress, macrophage infiltration, and fibrosis, and enhanced lipolysis in the renal interstitium. Fenofibrate inhibited palmitate-induced expression of profibrotic plasminogen activator inhibitor-1 (PAI-1) in cultured mesangial cells, and the expression of both monocyte chemoattractant protein-1 and PAI-1 in proximal tubular cells along with the overexpression of lipolytic enzymes. Thus, fenofibrate can attenuate lipotoxicity-induced glomerular and tubulointerstitial injuries, with enhancement of renal lipolysis. Whether amelioration of renal lipotoxicity by PPARα agonists will turn out to be a useful strategy against CKD will require direct testing.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Keiji
authors.initials: K
authors.lastname: Isshiki
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Sakaguchi
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: 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; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000008:administration & dosage
chemical_list: D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017931:DNA Primers; D004041:Dietary Fats; D047493:PPAR alpha; D012333:RNA, Messenger; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D012710:Serum Albumin, Bovine; D011345:Fenofibrate