Interferon-gamma inhibits experimental renal fibrosis

Background Recent evidence has implicated myofibroblasts as a cell type res ponsible for the laying down of extracellular matrix components during fibr osis in a number of organs. In this study, we examined the capacity of inte rferon-gamma (IFN-gamma) to inhibit the activation of fibroblasts to the my ofibroblastic phenotype and hence reduce the extent of renal scarring in th e rat subtotal nephrectomy (SNx) model using a novel method of intrarenal d elivery. Methods. Rats were divided into four groups: sham, SNx (group 1), SNx + dru g vehicle (group 2) and SNx + IFN-gamma (400 units/day; group 3) for 30 day s. Rats were sacrificed on days 15, 30, 45, and 90 following SNx. Results. Clinical data showed a marked reduction in proteinuria in the grou p treated with IFN-gamma (161 vs. 280 mg/24 hr by day 45, P < 0.01) and a p reservation of the creatinine clearance (1.16 vs. 0.84 ml/min by day 45, P < 0.05) when compared to the SNx or SNx + vehicle groups throughout the tim e course. Immunohistochemical staining for alpha-smooth muscle actin (alpha -SMA) revealed a reduction in myofibroblastic cell types (6.5 +/- 3.1% glom erular alpha-SMA in group 3 compared with 14.8 +/- 4.2% glomerular alpha-SM A in group 2, P < 0.05, 3.8 +/- 1.4% tubulointerstitial alpha-SMA in group 3 compared with 8.8 +/- 2.0% tubulointerstitial alpha-SMA in group 2 on day 45, P < 0.05). There was also a reduction in immunostaining for collagens III and IV in the IFN-gamma-treated group. Scoring for both glomerulosclero sis and tubulointerstitial fibrosis in the IFN-gamma group (group 3) was lo wer than the other two operated groups. Conclusions. We conclude that IFN-gamma, administered at a dose of 400 unit s/day, has a strong inhibitory effect on myofibroblasts and that as a possi ble result of this action, renal fibrosis is reduced and renal function is preserved in the rat SNx model. The IFN-gamma renoprotective effect lasted only for the extent of its administration and subsided when discontinued.