Early application of Met-RANTES ameliorates chronic allograft nephropathy

Kidney Int. 2002 Feb;61(2):676-85. doi: 10.1046/j.1523-1755.2002.00148.x.


Background: Initial insults to kidney allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to chronic allograft nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal allografts from long-term deterioration.

Methods: Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 microg/day, 200 microg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis.

Results: Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-B (PDGF-B).

Conclusions: Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

MeSH terms

  • Animals
  • Atrophy
  • Blood Pressure
  • Body Weight
  • Cell Division / drug effects
  • Chemokine CCL5 / analogs & derivatives*
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / pharmacology*
  • Fibrosis
  • Gene Expression / immunology
  • Glomerulosclerosis, Focal Segmental / drug therapy
  • Glomerulosclerosis, Focal Segmental / immunology
  • Glomerulosclerosis, Focal Segmental / surgery
  • Graft Rejection / drug therapy*
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Graft Survival / drug effects*
  • Graft Survival / immunology
  • Interleukin-1 / genetics
  • Interleukin-2 / genetics
  • Kidney Transplantation*
  • Kidney Tubules / pathology
  • Leukocytes / immunology
  • Male
  • RNA, Messenger / analysis
  • Rats
  • Rats, Inbred F344
  • Transplantation, Homologous
  • Tumor Necrosis Factor-alpha / genetics


  • Chemokine CCL5
  • Interleukin-1
  • Interleukin-2
  • RANTES, Met-
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha