Interferon-gamma inhibits experimental renal fibrosis

Kidney Int. 1999 Dec;56(6):2116-27. doi: 10.1046/j.1523-1755.1999.00775.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Animals
  • Antineoplastic Agents / analysis
  • Antineoplastic Agents / pharmacology*
  • Cicatrix / pathology
  • Cicatrix / prevention & control
  • Collagen / analysis
  • Creatinine / metabolism
  • Fibroblasts / chemistry
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • Fibrosis
  • Immunoenzyme Techniques
  • Infusion Pumps, Implantable
  • Interferon-gamma / analysis
  • Interferon-gamma / pharmacology*
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / pathology*
  • Kidney Diseases / prevention & control
  • Macrophages / chemistry
  • Male
  • Nephrectomy
  • Rats
  • Rats, Wistar

Substances

  • Actins
  • Antineoplastic Agents
  • Interferon-gamma
  • Collagen
  • Creatinine