Early application of Met-RANTES ameliorates chronic allograft nephropathy

Erwei Song, Hequn Zou, Yousheng Yao, Amanda Proudfoot, B. Antus, Shanying Lui, Lutz Jens, Uwe Heemann

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

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 μg/day, 200 μg/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-1β, tumor necrosis factor-α (TNF-α) 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-β (TGF-β) and platelet-derived growth factor-B (PDGF-B). Conclusions. Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mono-nuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

Original languageEnglish
Pages (from-to)676-685
Number of pages10
JournalKidney International
Volume61
Issue number2
DOIs
Publication statusPublished - 2002

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Allografts
T-Lymphocytes
Transplantation
Chemokine Receptors
Kidney
Tunica Intima
Proto-Oncogene Proteins c-sis
Transplants
Messenger RNA
Inbred F344 Rats
Transforming Growth Factors
Interleukin-1
Chemokines
Cyclosporine
Atrophy
Interleukin-2
Creatinine
Fibrosis
Arteries
Tumor Necrosis Factor-alpha

Keywords

  • Chemokine
  • Chronic rejection
  • Kidney transplantation
  • Leukocyte infiltration
  • Met-RANTES
  • Rats

ASJC Scopus subject areas

  • Nephrology

Cite this

Early application of Met-RANTES ameliorates chronic allograft nephropathy. / Song, Erwei; Zou, Hequn; Yao, Yousheng; Proudfoot, Amanda; Antus, B.; Lui, Shanying; Jens, Lutz; Heemann, Uwe.

In: Kidney International, Vol. 61, No. 2, 2002, p. 676-685.

Research output: Contribution to journalArticle

Song, E, Zou, H, Yao, Y, Proudfoot, A, Antus, B, Lui, S, Jens, L & Heemann, U 2002, 'Early application of Met-RANTES ameliorates chronic allograft nephropathy', Kidney International, vol. 61, no. 2, pp. 676-685. https://doi.org/10.1046/j.1523-1755.2002.00148.x
Song, Erwei ; Zou, Hequn ; Yao, Yousheng ; Proudfoot, Amanda ; Antus, B. ; Lui, Shanying ; Jens, Lutz ; Heemann, Uwe. / Early application of Met-RANTES ameliorates chronic allograft nephropathy. In: Kidney International. 2002 ; Vol. 61, No. 2. pp. 676-685.
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abstract = "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 μg/day, 200 μg/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-1β, tumor necrosis factor-α (TNF-α) 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-β (TGF-β) and platelet-derived growth factor-B (PDGF-B). Conclusions. Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mono-nuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.",
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T1 - Early application of Met-RANTES ameliorates chronic allograft nephropathy

AU - Song, Erwei

AU - Zou, Hequn

AU - Yao, Yousheng

AU - Proudfoot, Amanda

AU - Antus, B.

AU - Lui, Shanying

AU - Jens, Lutz

AU - Heemann, Uwe

PY - 2002

Y1 - 2002

N2 - 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 μg/day, 200 μg/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-1β, tumor necrosis factor-α (TNF-α) 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-β (TGF-β) and platelet-derived growth factor-B (PDGF-B). Conclusions. Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mono-nuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

AB - 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 μg/day, 200 μg/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-1β, tumor necrosis factor-α (TNF-α) 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-β (TGF-β) and platelet-derived growth factor-B (PDGF-B). Conclusions. Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mono-nuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

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KW - Chronic rejection

KW - Kidney transplantation

KW - Leukocyte infiltration

KW - Met-RANTES

KW - Rats

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