Blockade of angiotensin II with losartan attenuates transforming growth factor-beta1 inducible gene-h3 (betaig-h3) expression in a model of chronic cyclosporine nephrotoxicity

Nephron Exp Nephrol. 2005;99(1):e9-16. doi: 10.1159/000081793.


Background: We recently demonstrated that upregulation of the transforming growth factor (TGF)-beta1 inducible gene-h3 (betaig-h3) is associated with tubulointerstitial fibrosis (TIF) in a rat model of chronic cyclosporine A (CsA) nephrotoxicity. This study investigated the association between betaig-h3 expression and TIF during losartan treatment in this model.

Methods: Adult Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 4 weeks with vehicle (olive oil, 1 ml/kg), CsA (15 mg/kg) or both CsA and losartan (10 mg/kg in drinking water). The effect of losartan on betaig-h3 expression was evaluated using in situ hybridization, immunohistochemistry and immunoblotting. Histopathology, expressions of TGF-beta1 and intrarenal angiotensin II were compared across treatment groups.

Results: Concurrent administration of losartan significantly attenuated betaig-h3 mRNA and protein expression within the tubulointerstitium of CsA-treated kidneys. This was accompanied by the retardation of TIF (18 +/- 5 vs. 39 +/- 5%, p < 0.01 vs. CsA) and the expression of TGF-beta1 mRNA (336 +/- 49 vs. 685 +/- 63%, p < 0.01 vs. CsA) and the number of angiotensin II-positive glomeruli (18 +/- 5 vs. 38 +/- 6, p < 0.05 vs. CsA).

Conclusion: Losartan is capable of abrogating the upregulation of TGF-beta1 and betaig-h3 expression, and this is associated with attenuated tubulointerstitial fibrosis in chronic CsA nephrotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Blotting, Northern
  • Cyclosporine / toxicity*
  • Disease Models, Animal
  • Extracellular Matrix Proteins / biosynthesis*
  • Immunoblotting
  • Immunohistochemistry
  • Immunosuppressive Agents / toxicity*
  • In Situ Hybridization
  • Losartan / pharmacology*
  • Male
  • Nephritis, Interstitial / chemically induced*
  • Nephritis, Interstitial / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / biosynthesis*
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1
  • Up-Regulation


  • Angiotensin II Type 1 Receptor Blockers
  • Extracellular Matrix Proteins
  • Immunosuppressive Agents
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • betaIG-H3 protein
  • Cyclosporine
  • Losartan