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Accepted Manuscript
RESEARCH ARTICLE
Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish
Lauren Brilli Skvarca, Hwa In Han, Eugenel B. Espiritu, Maria A. Missinato, Elizabeth R. Rochon, Michael D. McDaniels, Abha S. Bais, Beth L. Roman, Joshua S. Waxman, Simon C. Watkins, Alan J. Davidson, Michael Tsang, Neil A. Hukriede
Disease Models & Mechanisms 2019 : dmm.037390 doi: 10.1242/dmm.037390 Published 19 March 2019
Lauren Brilli Skvarca
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USADepartment of Pathology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
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Hwa In Han
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
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Eugenel B. Espiritu
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
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Maria A. Missinato
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USASanford Burnham Prebys Medical Discovery Institute, La Jolla, California USA
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Elizabeth R. Rochon
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Michael D. McDaniels
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
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Abha S. Bais
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
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  • ORCID record for Abha S. Bais
Beth L. Roman
Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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Joshua S. Waxman
Heart Institute, Molecular Cardiovascular Biology Division, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA
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Simon C. Watkins
Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA, USA
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Alan J. Davidson
Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
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Michael Tsang
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
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Neil A. Hukriede
Department of Developmental Biology, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USACenter for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, USA
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  • For correspondence: hukriede@pitt.edu
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Abstract

Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI) that enhances renal recovery and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 expression, and lowers the number of infiltrating macrophages. Further, we find the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic.

  • Received October 3, 2018.
  • Accepted March 11, 2019.
  • © 2019. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Acute kidney injury
  • Macrophages
  • Renal proximal tubule cell
  • Cardiovascular
  • HDAC inhibitor
  • Therapeutic

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Accepted Manuscript
RESEARCH ARTICLE
Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish
Lauren Brilli Skvarca, Hwa In Han, Eugenel B. Espiritu, Maria A. Missinato, Elizabeth R. Rochon, Michael D. McDaniels, Abha S. Bais, Beth L. Roman, Joshua S. Waxman, Simon C. Watkins, Alan J. Davidson, Michael Tsang, Neil A. Hukriede
Disease Models & Mechanisms 2019 : dmm.037390 doi: 10.1242/dmm.037390 Published 19 March 2019
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Accepted Manuscript
RESEARCH ARTICLE
Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish
Lauren Brilli Skvarca, Hwa In Han, Eugenel B. Espiritu, Maria A. Missinato, Elizabeth R. Rochon, Michael D. McDaniels, Abha S. Bais, Beth L. Roman, Joshua S. Waxman, Simon C. Watkins, Alan J. Davidson, Michael Tsang, Neil A. Hukriede
Disease Models & Mechanisms 2019 : dmm.037390 doi: 10.1242/dmm.037390 Published 19 March 2019

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