title: Valproic acid attenuates renal fibrosis through the induction of autophagy.
abstract: BACKGROUND
  Renal fibrosis is a common pathological feature of the progression of chronic kidney disease. Although valproic acid (VPA) has been recently shown to induce autophagy, the effect of VPA-induced autophagy on renal fibrosis remains unknown. We, therefore, investigated whether VPA-induced autophagy suppresses renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO).
  
  
  METHODS
  Male C57BL/6 mice were divided into five groups (n = 8 per group): (1) sham group; (2) vehicle group; (3) VPA-treated group; (4) 3-methyladenine (3-MA; autophagy inhibitor)-treated group; and (5) VPA plus 3-MA-treated group. Mice underwent UUO and the kidneys were studied after 5 days. We also investigated the effect of VPA-induced autophagy on α-smooth muscle actin (α-SMA) in transforming growth factor (TGF)-β1-stimulated rat kidney fibroblasts and epithelial cells.
  
  
  RESULTS
  VPA attenuated renal fibrosis and induced autophagy in UUO mice, while 3-MA increased renal fibrosis and suppressed autophagy. In addition, the anti-fibrotic effect of VPA was diminished by 3-MA in UUO mice. In rat kidney fibroblasts and epithelial cells, VPA suppressed TGF-β1-stimulated α-SMA expression and induced autophagy. In contrast, 3-MA enhanced α-SMA expression while inhibiting autophagy. Furthermore, the combined use of VPA and 3-MA treatments increased the expression of α-SMA compared with VPA treatment alone in TGF-β1-stimulated rat kidney fibroblasts and epithelial cells, which was accompanied by the inhibition of autophagy.
  
  
  CONCLUSIONS
  These findings suggest that VPA may be a candidate drug for the treatment of renal fibrosis through the induction of autophagy.
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kawaoka
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan. sdoi@hiroshima-u.ac.jp.|Department of Blood Purification, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan. sdoi@hiroshima-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Doi
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Nakashima
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000199:Actins / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000199:Actins; D000225:Adenine; D024042:Collagen Type I; D008869:Microtubule-Associated Proteins; D053773:Transforming Growth Factor beta1; D014635:Valproic Acid; C480860:Map1lc3b protein, mouse; C508960:TGFB1 protein, human; C544013:alpha-smooth muscle actin, mouse; C498862:Acta2 protein, rat; C025946:3-methyladenine
keywords: Autophagy; Renal fibrosis; TGF-β1; Valproic acid