title: Sirtuin 1 activation stimulates mitochondrial biogenesis and attenuates renal injury after ischemia-reperfusion.
abstract: BACKGROUND
  Renal ischemia-reperfusion (I/R) is a major contributor to delayed graft function after renal transplantation. The pathophysiology of I/R can be summarized by a primary energy deficit during ischemia and a secondary phase of oxidative stress and inflammation. Sirtuin 1 is an energy-sensing enzyme involved in regulating multiple cellular functions. We hypothesized that stimulating Sirtuin 1 would increase mitochondrial biogenesis thereby enhancing energy metabolism and attenuating I/R-induced renal injury.
  
  
  METHODS
  Adult male rats were subjected to 60 min of bilateral renal pedicle clamping. SRT1720 (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously at reperfusion. Blood and renal tissues were collected 24 hr after reperfusion.
  
  
  RESULTS
  Posttreatment with SRT1720 significantly improved renal histologic architecture, decreased apoptosis, and reduced serum aspartate aminotransferase and creatinine levels compared to the vehicle. Renal adenosine triphosphate (ATP) levels were reduced by 48% after I/R, whereas SRT1720 restored ATP to 77% of control. Further, SRT1720 reversed the loss of renal mitochondrial mass induced by I/R supported by an increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and its downstream mediators. SRT1720 also increased ATP levels and mitochondrial mass in human renal HK-2 cells. Moreover, SRT1720 decreased the levels of malondialdehyde, nitrotyrosine, and inducible nitric oxide synthase expression compared to the vehicle. A marked decrease in macrophage infiltration by SRT1720 treatment was associated with a decrease in tumor necrosis factor-α expression and a decrease in IκB-α degradation and nuclear factor-κB phosphorylation after I/R.
  
  
  CONCLUSIONS
  SRT1720 treatment enhanced energy metabolism by stimulating mitochondrial biogenesis as well as decreasing nitrosative stress and inflammation, thereby attenuating I/R-induced renal injury.
authors.affiliation: 1 The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY. 2 Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. 3 Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY. 4 Department of Pathology, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. 5 Address correspondence to: Ping Wang, M.D., Center for Translational Research, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030.
authors.forename: Adam
authors.initials: A
authors.lastname: Khader
authors.forename: Weng-Lang
authors.initials: WL
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Kuncewitch
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Jose M
authors.initials: JM
authors.lastname: Prince
authors.forename: Jaya R
authors.initials: JR
authors.lastname: Asirvatham
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nicastro
authors.forename: Gene F
authors.initials: GF
authors.lastname: Coppa
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D063269:Mitochondrial Turnover / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D006576:Heterocyclic Compounds, 4 or More Rings; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; C525422:SRT1720; C488368:Sirt1 protein, rat; D056564:Sirtuin 1