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


CONCLUSIONS
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.
Sun
Bo Kyung
BK
Department of Internal Medicine, The Catholic University of Korea, Seoul.
Li
Can
C
Lim
Sun Woo
SW
Choi
Bum Soon
BS
Lee
Suk Hee
SH
Kim
In San
IS
Kim
Yong Soo
YS
Bang
Byung Kee
BK
Yang
Chul Woo
CW
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D016572:Cyclosporine / Q000633:toxicity*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D017403:In Situ Hybridization; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D000099222:betaIG-H3 Protein
D047228:Angiotensin II Type 1 Receptor Blockers; D016572:Cyclosporine; D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D019808:Losartan; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C508962:Tgfb1 protein, rat