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ResearchIn-Press PreviewImmunologyNephrology Open Access | 10.1172/jci.insight.158523

Remote ischemic preconditioning causes transient cell-cycle arrest and renal protection by a NF-kB-dependent Sema5B pathway

Jan Rossaint,1 Melanie Meersch,2 Katharina Thomas,3 Sina Mersmann,3 Martin Lehmann,3 Jennifer Skupski,3 Tobias Tekath,4 Peter Rosenberger,5 John A. Kellum,6 Hermann Pavenstädt,7 and Alexander Zarbock8

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Rossaint, J. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Meersch, M. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Thomas, K. in: JCI | PubMed | Google Scholar |

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Mersmann, S. in: JCI | PubMed | Google Scholar |

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Lehmann, M. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Skupski, J. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Tekath, T. in: JCI | PubMed | Google Scholar |

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Rosenberger, P. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Kellum, J. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Pavenstädt, H. in: JCI | PubMed | Google Scholar

1Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Muenster, Münster, Germany

2Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

3Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

4Institute of Medical Informatics, University of Münster, Münster, Germany

5Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, Tübingen, Germany

6Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States of America

7Department of Nephrology, Internal Medicine D, University of Münster, Münster, Germany

8Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany

Find articles by Zarbock, A. in: JCI | PubMed | Google Scholar

Published June 21, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.158523.
Copyright © 2022, Rossaint et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 21, 2022 - Version history
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Abstract

Acute kidney injury increases morbidity and mortality and previous studies have shown that remote ischemic preconditioning (RIPC) reduces the risk of acute kidney injury after cardiac surgery. RIPC increases urinary HMGB1 (high mobility group box protein-1) levels in patients which correlates with kidney protection. Here, we show that RIPC reduces renal ischemia-reperfusion injury and improves kidney function in mice. Mechanistically, RIPC increases HMGB1 levels in the plasma and urine and HMGB1 binds to Toll-like receptor 4 (TLR4) on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on non-renal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPK⍺ and NF-kB, which induces the upregulation of Sema5b that triggers a transient, protective G1 cell-cycle arrest. In cardiac surgery patients at high risk for postoperative acute kidney injury, increased HMGB1 and Sema5b levels after RIPC were associated with renal protection after surgery. The results may help to develop future clinical treatment options for acute kidney injury.

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