Inhibitory effect of pravastatin on transforming growth factor beta1-inducible gene h3 expression in a rat model of chronic cyclosporine nephropathy.
OBJECTIVE
Overexpression of transforming growth factor beta1-inducible gene h3 (betaig-h3) is associated with renal scarring in several models of renal disease. We investigated the inhibitory effect of pravastatin on betaig-h3 expression in a rat model of chronic cyclosporin A (CsA)-induced nephropathy.


METHODS
Adult Sprague Dawley rats kept on a low salt 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 pravastatin (20 mg/kg in drinking water). The effect of pravastatin on betaig-h3 expression was evaluated using in situ hybridization, immunohistochemistry, and immunoblotting. Functional parameters, histopathology (tubulointerstitial fibrosis, TIF, and arteriolopathy), and levels of transforming growth factor beta1 (TGF-beta1) and endothelial nitric oxide synthase were compared for the different treatment groups.


RESULTS
Co-administration of pravastatin significantly inhibited betaig-h3 mRNA production and gene expression within the tubulointerstitium of the CsA-treated kidneys, and this paralleled an attenuation of TIF (12.7 +/- 2.2 vs. 35.9 +/- 5.4%, p < 0.01 vs. CsA) and the expression of TGF-beta1 mRNA (279 +/- 40 vs. 719 +/- 85%, p < 0.01 vs. CsA). Pravastatin treatment reduced endothelial nitric oxide synthase protein levels and reversed the renal dysfunction caused by CsA. Neither CsA nor pravastatin affected total serum cholesterol or triglyceride levels in the treatment groups.


CONCLUSIONS
Pravastatin thus effectively abrogated the upregulation of betaig-h3 gene expression and associated TGF-beta1 production, and this was associated with attenuated TIF in this model of chronic CsA-induced nephropathy.
Li
Can
C
Department of Internal Medicine, Xenotransplantation Center, KangNam St. Mary's Hospital, Seoul, Korea.
Lim
Sun Woo
SW
Choi
Bum Soon
BS
Lee
Suk Hee
SH
Cha
Jung Ho
JH
Kim
In San
IS
Kim
Jin
J
Yang
Chul Woo
CW
D000818:Animals; D015152:Blotting, Northern; D016572:Cyclosporine; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008297:Male; D009400:Nephrosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000187:drug effects*; D053773:Transforming Growth Factor beta1
D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin