title: Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress is emerging as an important factor in the development of organ fibrosis. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. SIRT1, a class III histone deacetylase, has been found to exert beneficial effects in kidney diseases. However, it is largely unknown whether and how SIRT1 suppresses the ER stress. We postulated that upregulation of SIRT1 would suppress the ER stress through induction of heme oxygenase-1 (HO-1) and thioredoxin.
  
  
  METHODS
  HK-2 tubular cells, experimental mouse models of tunicamycin (TM)-induced ER stress and unilateral ureteral obstruction (UUO) were used. Expression of ER stress-induced protein was measured by Western blot analysis and immunohistochemical staining. ER stress was induced by chemical ER stress inducers [TM [,]thapsigargin (TG)] and non-chemical inducers such as angiotensin II, aldosterone, high glucose and albumin.
  
  
  RESULTS
  SIRT1 activator (SRT1720) induced SIRT1 expression in a time- and dose-dependent manner in HK-2 cells. SRT1720 suppressed the TM- or TG-induced ER stress, as shown by inhibition of TM- or TG-induced upregulation of glucose-related protein 78 (GRP78), phosphor-specific eukaryotic translation initiation factor-2α and C/EBP homologous protein through HO-1 and thioredoxin, which were abolished by pretreatment with SIRT1 inhibitor (sirtinol). SRT1720 also suppressed the ER stress induced by angiotensin II, aldosterone, high glucose and albumin. In animal studies, treatment with SRT1720 reduced the tubular expression of GRP78 and increased the expression of HO-1 and thioredoxin. SRT1720 also reduced the UUO-induced renal fibrosis.
  
  
  CONCLUSIONS
  SIRT1 may serve as a promising therapeutic target by reducing ER stress and fibrosis.
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Jai Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Hyosang
authors.initials: H
authors.lastname: Kim
authors.forename: Chung Hee
authors.initials: CH
authors.lastname: Baek
authors.forename: Raymond Bok
authors.initials: RB
authors.lastname: Lee
authors.forename: Won Seok
authors.initials: WS
authors.lastname: Yang
authors.forename: Sang Koo
authors.initials: SK
authors.lastname: Lee
mesh_terms: D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005355:Fibrosis / Q000517:prevention & control; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007674:Kidney Diseases / Q000517:prevention & control*; D056564:Sirtuin 1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; C000717248:Hspa5 protein, mouse; C525422:SRT1720; C447939:SIRT1 protein, human; D056564:Sirtuin 1