Interferon-gamma inhibits experimental renal fibrosis.
Interferon-gamma inhibits experimental renal fibrosis.


BACKGROUND
Recent evidence has implicated myofibroblasts as a cell type responsible for the laying down of extracellular matrix components during fibrosis in a number of organs. In this study, we examined the capacity of interferon-gamma (IFN-gamma) to inhibit the activation of fibroblasts to the myofibroblastic phenotype and hence reduce the extent of renal scarring in the rat subtotal nephrectomy (SNx) model using a novel method of intrarenal delivery.


METHODS
Rats were divided into four groups: sham, SNx (group 1), SNx + drug vehicle (group 2) and SNx + IFN-gamma (400 units/day; group 3) for 30 days. Rats were sacrificed on days 15, 30, 45, and 90 following SNx.


RESULTS
Clinical data showed a marked reduction in proteinuria in the group treated with IFN-gamma (161 vs. 280 mg/24 hr by day 45, P < 0.01) and a preservation 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 time course. Immunohistochemical staining for alpha-smooth muscle actin (alpha-SMA) revealed a reduction in myofibroblastic cell types (6.5 +/- 3.1% glomerular alpha-SMA in group 3 compared with 14.8 +/- 4.2% glomerular alpha-SMA 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 glomerulosclerosis and tubulointerstitial fibrosis in the IFN-gamma group (group 3) was lower than the other two operated groups.


CONCLUSIONS
We conclude that IFN-gamma, administered at a dose of 400 units/day, has a strong inhibitory effect on myofibroblasts and that as a possible 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.
Oldroyd
S D
SD
Division of Clinical Sciences NGH, Sheffield Kidney Institute, University of Sheffield, Northern General Hospital, England, United Kingdom. s.d.oldroyd@sheffield.ac.uk
Thomas
G L
GL
Gabbiani
G
G
El Nahas
A M
AM
D000199:Actins / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000494:pharmacology*; D002921:Cicatrix / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000032:analysis; D003404:Creatinine / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D007124:Immunoenzyme Techniques; D015918:Infusion Pumps, Implantable; D007371:Interferon-gamma / Q000032:analysis / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology* / Q000517:prevention & control; D008264:Macrophages / Q000737:chemistry; D008297:Male; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar
D000199:Actins; D000970:Antineoplastic Agents; D007371:Interferon-gamma; D003094:Collagen; D003404:Creatinine