title: Klotho suppresses the renin-angiotensin system in adriamycin nephropathy.
abstract: BACKGROUND
  Klotho protein interacts with the transforming growth factor β (TGF-β) receptor and Wnt, which contribute to the progression of renal disease, inhibiting their signals. Renal and circulating klotho levels are diminished in chronic kidney disease.
  
  
  METHODS
  Experiments were performed to assess whether supplementation of klotho protein could have protective effects on the kidney. Rats were injected with adriamycin (5 mg/kg) and divided into three groups: those treated with vehicle, those treated with klotho protein and those treated with klotho plus 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD). Rats without adriamycin treatment were used as a control.
  
  
  RESULTS
  Adriamycin reduced the serum klotho concentration and renal expression of klotho and E-cadherin. Adriamycin also increased the renal expression of Wnt, TGF-β, and angiotensinogen, as well as the renal abundance of β-catenin and angiotensin II. Klotho supplementation suppressed adriamycin-induced elevations of β-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of β-catenin and angiotensin II as well as the expression of TGF-β and angiotensinogen without affecting E-cadherin.
  
  
  CONCLUSIONS
  Our data indicate that Wnt is involved in the pathogenesis of adriamycin nephropathy. Furthermore, klotho supplementation inhibited Wnt signaling, ameliorating renal angiotensin II. Finally, klotho protein appears to suppress epithelial-mesenchymal transition by inhibiting TGF-β and Wnt signaling.
authors: Department of Medicine, International University of Health and Welfare, 8-10-16 Akasaka, Minato, Tokyo 107-0052, Japan.
authors: Tsuneo
authors: T
authors: Takenaka
authors: Department of Nephrology, Saitama Medical University, Iruma, Saitama, Japan.
authors: Tsutomu
authors: T
authors: Inoue
authors: Department of Nephrology, Saitama Medical University, Iruma, Saitama, Japan.
authors: Takashi
authors: T
authors: Miyazaki
authors: Department of Medicine, International University of Health and Welfare, 8-10-16 Akasaka, Minato, Tokyo 107-0052, Japan.
authors: Hiroyuki
authors: H
authors: Kobori
authors: Department of Pharmacology, Kagawa University, Kida, Kagawa, Japan.
authors: Akira
authors: A
authors: Nishiyama
authors: Department of Clinical Chemistry, Kitasato University, Sagamihara, Kanagawa, Japan.
authors: Naohito
authors: N
authors: Ishii
authors: Blood Purification Center, Keio University, Shinjuku, Tokyo, Japan.
authors: Matsuhiko
authors: M
authors: Hayashi
authors: Department of Nephrology, Saitama Medical University, Iruma, Saitama, Japan.
authors: Hiromichi
authors: H
authors: Suzuki
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015820:Cadherins / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D058750:Epithelial-Mesenchymal Transition; D005966:Glucuronidase / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000090265:Klotho Proteins; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction; D013830:Thiadiazoles / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000903:Antibiotics, Antineoplastic; D015820:Cadherins; D018125:Receptors, Transforming Growth Factor beta; D013830:Thiadiazoles; D051176:beta Catenin; D004317:Doxorubicin; D038362:Glycogen Synthase Kinase 3; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: TRPC6; fibrosis; nephrin; oxidative stress; β-catenin