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Dis Model Mech. 2019 Apr 5;12(4). pii: dmm037390. doi: 10.1242/dmm.037390.

Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish.

Author information

1
Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
2
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
3
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
4
Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5
Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
6
Heart Institute, Molecular Cardiovascular Biology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
7
Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA 15261, USA.
8
Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
9
Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA hukriede@pitt.edu.
10
Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

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), as an enhancer of 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 (Kim-1) expression, and lowers the number of infiltrating macrophages. Further, we found that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate that 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.This article has an associated First Person interview with the joint first authors of the paper.

KEYWORDS:

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

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