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

Nephrol Dial Transplant. 2011 Mar;26(3):800-13. doi: 10.1093/ndt/gfq537. Epub 2010 Sep 2.

Abstract

Background: The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin-angiotensin 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 transcription-polymerase 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Aging / drug effects*
  • Angiotensin II / antagonists & inhibitors*
  • Animals
  • Blotting, Western
  • Chronic Disease
  • Cyclosporine / adverse effects*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / urine
  • Disease Models, Animal*
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • Immunoenzyme Techniques
  • Immunosuppressive Agents / adverse effects*
  • Kidney Diseases / chemically induced
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Male
  • Mice
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation
  • Vasoconstrictor Agents / antagonists & inhibitors

Substances

  • Immunosuppressive Agents
  • RNA, Messenger
  • Vasoconstrictor Agents
  • Angiotensin II
  • Cyclosporine
  • 8-Hydroxy-2'-Deoxyguanosine
  • Glucuronidase
  • klotho protein
  • Deoxyguanosine