title: Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice.
abstract: BACKGROUND
  Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy.
  
  
  METHODS
  Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured.
  
  
  RESULTS
  We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines.
  
  
  CONCLUSIONS
  Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kadoya
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. msatoh@med.kawasaki-m.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Haruna
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D018836:Inflammation Mediators / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D014162:Transfection
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005966:Glucuronidase; D000090265:Klotho Proteins; D002154:Calpain; D003849:Deoxyguanosine; D005947:Glucose
keywords: Albuminuria; Calpain; Diabetes; Klotho; Macrophage