Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation
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- Bernd Krüger
- Division of Nephrology and
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- Stefanie Krick
- Division of Nephrology and
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- Navdeep Dhillon
- Division of Nephrology and
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- Susan M. Lerner
- Transplantion Institute, Mount Sinai School of Medicine, New York, NY 10029;
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- Scott Ames
- Transplantion Institute, Mount Sinai School of Medicine, New York, NY 10029;
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- Jonathan S. Bromberg
- Transplantion Institute, Mount Sinai School of Medicine, New York, NY 10029;
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- Marvin Lin
- Division of Nephrology and
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- Liron Walsh
- Division of Nephrology and
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- John Vella
- Division of Nephrology, Maine Medical Center, Portland, ME 04102;
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- Michael Fischereder
- Medizinische Poliklinik Innenstadt München, Ludwig-Maximilians-Universität München, Munich, Germany;
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- Bernhard K. Krämer
- Marienhospital Herne, Medizinische Klinik I, Klinikum der Ruhr-Universität Bochum, Germany; and
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- Robert B. Colvin
- Pathology Research Massachusetts General Hospital, Boston MA 02114
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- Peter S. Heeger
- Division of Nephrology and
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- Barbara T. Murphy
- Division of Nephrology and
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- Bernd Schröppel
- Division of Nephrology and
書誌事項
- 公開日
- 2009-03-03
- DOI
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- 10.1073/pnas.0810169106
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p>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 TNFα, 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.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 106 (9), 3390-3395, 2009-03-03
Proceedings of the National Academy of Sciences