Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation
被引:271
作者:
Krueger, Bernd
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Klinikum Ruhr Univ Bochum, Med Klin 1, Marienhosp Herne, Bochum, GermanyMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Krueger, Bernd
[1
,5
]
Krick, Stefanie
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Krick, Stefanie
[1
]
Dhillon, Navdeep
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Dhillon, Navdeep
[1
]
Lerner, Susan M.
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机构:
Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Lerner, Susan M.
[2
]
Ames, Scott
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机构:
Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Ames, Scott
[2
]
Bromberg, Jonathan S.
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机构:
Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Bromberg, Jonathan S.
[2
]
Lin, Marvin
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Lin, Marvin
[1
]
Walsh, Liron
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Walsh, Liron
[1
]
Vella, John
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机构:
Maine Med Ctr, Div Nephrol, Portland, ME 04102 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Vella, John
[3
]
Fischereder, Michael
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机构:
Univ Munich, Med Poliklin Innenstadt Munchen, Munich, GermanyMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Fischereder, Michael
[4
]
Kraemer, Bernhard K.
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机构:
Klinikum Ruhr Univ Bochum, Med Klin 1, Marienhosp Herne, Bochum, GermanyMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Kraemer, Bernhard K.
[5
]
Colvin, Robert B.
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机构:
Pathol Res Massachusetts Gen Hosp, Boston, MA 02114 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Colvin, Robert B.
[6
]
Heeger, Peter S.
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h-index: 0
机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Heeger, Peter S.
[1
,2
]
Murphy, Barbara T.
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Murphy, Barbara T.
[1
,2
]
Schroeppel, Bernd
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机构:
Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USAMt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
Schroeppel, Bernd
[1
,2
]
机构:
[1] Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
[2] Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USA
[3] Maine Med Ctr, Div Nephrol, Portland, ME 04102 USA
[4] Univ Munich, Med Poliklin Innenstadt Munchen, Munich, Germany
While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNF alpha, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.
机构:
St Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
St Louis Univ, Dept Med, St Louis, MO 63103 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
El-Achkar, Tarek M.
Wu, Xue-Ru
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机构:
NYU, Sch Med, Dept Urol, New York, NY 10003 USA
NYU, Sch Med, Dept Pathol, New York, NY 10003 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
Wu, Xue-Ru
Rauchman, Michael
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机构:
St Louis Univ, Dept Med, St Louis, MO 63103 USA
St Louis Univ, Dept Biochem, St Louis, MO 63103 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
Rauchman, Michael
McCracken, Ruth
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机构:
St Louis Univ, Dept Med, St Louis, MO 63103 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
McCracken, Ruth
Kiefer, Susan
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h-index: 0
机构:St Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
Kiefer, Susan
Dagher, Pierre C.
论文数: 0引用数: 0
h-index: 0
机构:
Indiana Univ, Dept Med, Indianapolis, IN USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
机构:
St Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
St Louis Univ, Dept Med, St Louis, MO 63103 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
El-Achkar, Tarek M.
Wu, Xue-Ru
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Dept Urol, New York, NY 10003 USA
NYU, Sch Med, Dept Pathol, New York, NY 10003 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
Wu, Xue-Ru
Rauchman, Michael
论文数: 0引用数: 0
h-index: 0
机构:
St Louis Univ, Dept Med, St Louis, MO 63103 USA
St Louis Univ, Dept Biochem, St Louis, MO 63103 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
Rauchman, Michael
McCracken, Ruth
论文数: 0引用数: 0
h-index: 0
机构:
St Louis Univ, Dept Med, St Louis, MO 63103 USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
McCracken, Ruth
Kiefer, Susan
论文数: 0引用数: 0
h-index: 0
机构:St Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA
Kiefer, Susan
Dagher, Pierre C.
论文数: 0引用数: 0
h-index: 0
机构:
Indiana Univ, Dept Med, Indianapolis, IN USASt Louis VA Med Ctr, Div Nephrol, St Louis, MO 63106 USA