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ResearchIn-Press PreviewNephrology Open Access | 10.1172/jci.insight.173144

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Min Yang,1 Lauren N. Lopez,1 Maya Brewer,1 Rachel Delgado,1 Anna Menshikh,1 Kelly Clouthier,1 Yuantee Zhu,2 Thitinee Vanichapol,3 Haichun Yang,4 Raymond C. Harris,1 Leslie Gewin,5 Craig R. Brooks,1 Alan J. Davidson,6 and Mark de Caestecker1

1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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

1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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

1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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1Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States of America

3Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

4Department of Pathology, Vanderbildt University Medical Center, Nashville, United States of America

5Department of Medicine, Washington University, St. Louis, St. Louis, United States of America

6University of Auckland, Auckland, New Zealand

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Published September 12, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.173144.
Copyright © 2023, Yang 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 September 12, 2023 - Version history
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Abstract

Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development, but in the adult kidney is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI), and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker, Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1 dependent apoptotic cell clearance, or efferocytosis, and this was associated with de-differentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate the functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.

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graphical abstract
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Version history
  • Version 1 (September 12, 2023): In-Press Preview
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