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Early application of Met-RANTES ameliorates chronic allograft nephropathy
Erwei Song1, Hequn Zou, Yousheng Yao
1Department of Nephrology, University Hospital, Essen, Germany.
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.
Insights
Early blockade of chemokine receptors with Met-RANTES significantly reduced mononuclear cell infiltration and chronic allograft nephropathy progression in renal transplants. This treatment protected grafts from long-term deterioration.
Area of Science:
- Nephrology
- Immunology
- Transplantation Biology
Background:
- Chronic allograft nephropathy is driven by inflammatory cell infiltration in kidney transplants.
- Chemokines, like RANTES (regulated upon activation, normal T cell expressed), mediate this inflammatory cell recruitment.
- Targeting chemokine pathways offers a potential strategy to prevent graft damage.
Purpose of the Study:
- To investigate the efficacy of early Met-RANTES treatment in preventing chronic allograft nephropathy.
- To assess the impact of Met-RANTES on inflammatory cell infiltration and graft histology.
Main Methods:
- Lewis rats received Fisher (F344) kidney allografts and were treated with cyclosporine A and either Met-RANTES or vehicle.
- Grafts were analyzed histologically, immunohistologically, and molecularly at 2 and 28 weeks post-transplantation.
Main Results:
- Met-RANTES reduced early lymphocyte and macrophage infiltration and pro-inflammatory cytokine mRNA expression (IL-2, IL-1beta, TNF-alpha, RANTES).
- Long-term treatment ameliorated glomerulosclerosis, fibrosis, atrophy, and vascular intimal proliferation, and reduced proteinuria.
- Creatinine clearance remained unaffected; TGF-beta and PDGF-B mRNA expression were suppressed.
Conclusions:
- Early Met-RANTES administration effectively blocks chemokine receptor activity, reducing early inflammatory cell infiltration and activation.
- This blockade significantly mitigates the progression of chronic allograft nephropathy, offering a protective effect on renal allografts.