Klotho suppresses the renin-angiotensin system in adriamycin nephropathy

Tsuneo Takenaka, Tsutomu Inoue, Takashi Miyazaki, Hiroyuki Kobori, Akira Nishiyama, Naohito Ishii, Matsuhiko Hayashi, Hiromichi Suzuki

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Backgrounds: 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 b-catenin and angiotensin II. Klotho supplementation suppressed adriamycininduced elevations of b-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of b-catenin and angiotensin II as well as the expression of TGF-β and angiotensinogen without affecting Ecadherin. 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.

Original languageEnglish
Pages (from-to)791-800
Number of pages10
JournalNephrology Dialysis Transplantation
Volume32
Issue number5
DOIs
Publication statusPublished - 2017 May 1

Keywords

  • b-catenin
  • fibrosis
  • nephrin
  • oxidative stress
  • TRPC6

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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    Takenaka, T., Inoue, T., Miyazaki, T., Kobori, H., Nishiyama, A., Ishii, N., Hayashi, M., & Suzuki, H. (2017). Klotho suppresses the renin-angiotensin system in adriamycin nephropathy. Nephrology Dialysis Transplantation, 32(5), 791-800. https://doi.org/10.1093/ndt/gfw340