22 November 2005
Background/Aims: Overexpression of transforming growth factor β1-inducible gene h3 (βig-h3) is associated with renal scarring in several models of renal disease. We investigated the inhibitory effect of pravastatin on βig-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 βig-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 β1 (TGF-β1) and endothelial nitric oxide synthase were compared for the different treatment groups. Results: Co-administration of pravastatin significantly inhibited βig-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-β1 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. Conclusion: Pravastatin thus effectively abrogated the upregulation of βig-h3 gene expression and associated TGF-β1 production, and this was associated with attenuated TIF in this model of chronic CsA-induced nephropathy.