Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy

Hye Eun Yoon, Jung Yeon Ghee, Shangguo Piao, Ji Hyun Song, Dong He Han, Sol Kim, Naro Ohashi, Hiroyuki Kobori, Makoto Kuro-O, Chul Woo Yang

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Abstract

Background: The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of reninangiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury.Methods. Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcriptionpolymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG).Results. CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion.Conclusions. Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.

Original languageEnglish (US)
Pages (from-to)800-813
Number of pages14
JournalNephrology Dialysis Transplantation
Volume26
Issue number3
DOIs
Publication statusPublished - Mar 2011

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Keywords

  • cyclosporine
  • kidney transplantation
  • nephrotoxicity
  • reninangiotensin system
  • senescence

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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