title: Klotho Deficiency Aggravates Tacrolimus-Induced Renal Injury via the Phosphatidylinositol 3-Kinase-Akt-Forkhead Box Protein O Pathway.
abstract: Klotho is highly expressed in the kidney, is present in the circulation and urine, and has protective effects against various renal injuries. We examined whether reduced Klotho expression affects tacrolimus (Tac)-induced renal injury in an experimental model of chronic Tac nephropathy.
  
  
  
  First, we evaluated the association between the Tac dose and Klotho expression by giving different doses of Tac (0.25, 0.5, and 1 mg/kg) to wild-type (WT) mice for 4 weeks. Second, we compared Klotho levels, renal function, fibrosis, and apoptosis between WT mice and Klotho heterozygous (HT) mice in an experimental model of chronic Tac nephropathy. Third, we examined whether the oxidative stress and signaling pathway are involved in the protection by Klotho against Tac-induced renal injury.
  
  
  
  Klotho levels in renal tissue and urine were reduced in a dose-dependent manner in Tac-treated WT mice. Tac-treated HT mice showed lower levels of Klotho in the renal cortex and urine, and higher serum creatinine level, fibrosis, and apoptosis compared with WT mice. Treatment of Tac to WT mice increased markers of oxidative stress such as phosphatidylinositol 3-kinase (PI3K)-Akt and Forkhead box protein O (FoxO) 3a phosphorylation but decreased FoxO1 dephosphorylation. These effects were greater in HT mice. HT mice exhibited a much lower level of manganese superoxide dismutase level and higher level of Bim, target genes of FoxOs, compared with the levels in WT mice.
  
  
  
  Reduced Klotho expression aggravates Tac-induced renal injury via the PI3K-Akt-FoxO pathway.
authors.affiliation: Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Long
authors.initials: L
authors.lastname: Jin
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000378:metabolism; D016559:Tacrolimus
chemical_list: D051858:Forkhead Transcription Factors; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D005966:Glucuronidase; D000090265:Klotho Proteins; D016559:Tacrolimus