title: Influence of N-acetylcysteine on Klotho expression and its signaling pathway in experimental model of chronic cyclosporine nephropathy in mice.
abstract: BACKGROUND
  Cyclosporine A (CsA)-associated oxidative stress has been proposed as an important mechanism of renal injury. This study was designed to examine whether N-acetylcysteine (NAC), a well-known antioxidant, affects Klotho, antiaging gene, expression and its signaling pathway in an experimental model of chronic CsA nephropathy.
  
  
  METHODS
  Mice maintained on a low-sodium diet were given vehicle (olive oil, 1 mL/kg/day), CsA (30 mg/kg/day), NAC (150 mg/kg/day), or a combination of CsA and NAC for 4 weeks. The effect of NAC on CsA-induced renal injury was evaluated with basic parameters, histopathology, and markers of oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion and manganese superoxide dismutase (MnSOD) expression]. The influence of NAC on Klotho and its signal pathway (p-AKT and p-FoxO1) in CsA-treated mouse kidney was evaluated with immunohistochemistry and/or immunoblot.
  
  
  RESULTS
  Concomitant administration of CsA and NAC significantly improved renal function and attenuated tubulointerstitial fibrosis, and these changes were accompanied by decreased urinary 8-OHdG level and increased MnSOD expression. NAC treatment preserved Klotho gene expression compared with CsA treatment alone (P < 0.05), and this correlated with urinary 8-OHdG excretion (r = -0.934) and MnSOD expression (r = 0.873, P < 0.001 for both). Concomitant treatment of CsA and NAC translocated FoxO1 from the cytoplasm to the nucleus, implicating dephosphorylation of FoxO1 by NAC in p-AKT/p-FoxO1 pathway.
  
  
  CONCLUSIONS
  NAC treatment preserves Klotho expression and modifies p-AKT/p-FoxO1 pathway in chronic CsA nephropathy.
authors.affiliation: Transplant Research Center, Convergent Research Consortium in Immunologic Disease, The Catholic University of Korea, Seoul, Korea.
authors.forename: Shang Guo
authors.initials: SG
authors.lastname: Piao
authors.forename: Seok Hui
authors.initials: SH
authors.lastname: Kang
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.forename: Byung Ha
authors.initials: BH
authors.lastname: Chung
authors.forename: Kyoung Chan
authors.initials: KC
authors.lastname: Doh
authors.forename: Seong Beom
authors.initials: SB
authors.lastname: Heo
authors.forename: Long
authors.initials: L
authors.lastname: Jin
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002908:Chronic Disease; D016572:Cyclosporine / Q000009:adverse effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D005966:Glucuronidase; D000090265:Klotho Proteins; D003849:Deoxyguanosine; D000111:Acetylcysteine