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

Lauren Brilli Skvarca,Neil A Hukriede,Simon C Watkins,Michael D Mcdaniels,Maria A Missinato,Elizabeth R Rochon,Alan J Davidson,Hwa In Han,Joshua S Waxman,Abha S Bais,Eugenel B Espiritu,Beth L Roman,Michael Tsang

doi:10.1242/dmm.037390

Abstract

ABSTRACTAcute 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.

Highlights

Acute kidney injury (AKI) is a rapid decline in renal function that results in 2 million deaths annually worldwide and accounts for billions in US healthcare costs (Chertow et al, 2005; Murugan and Kellum, 2011)
PTBA increases renal tubular epithelial cells (RTECs) dedifferentiation and repair responses post-AKI We have previously shown that PTBA treatment increases RTEC proliferation in a zebrafish larval model of AKI (Cianciolo Cosentino et al, 2013; Hentschel et al, 2005)
To assess whether PTBA increases the population of cells that drive AKI mediated proliferation, we examined whether UPHD25 treatment increases Pax2a expression after renal injury, since Pax2a is a well-known marker of gene reactivation during RTEC dedifferentiation

Summary

Introduction

Acute kidney injury (AKI) is a rapid decline in renal function that results in 2 million deaths annually worldwide and accounts for billions in US healthcare costs (Chertow et al, 2005; Murugan and Kellum, 2011). Since renal biopsies are not often performed in AKI patients, the underlying physiology and histopathology have been largely defined using rodent models (Lieberthal and Nigam, 2000; Murugan and Kellum, 2011) These studies have identified key cellular players during AKI events, including roles for the tubular epithelium and the immune system. Damaged renal tubular epithelial cells (RTECs) undergo dedifferentiation to a mesenchymal state by reactivating pathways common during early renal development (Benigni et al, 2010; Cirio et al, 2014; Imgrund et al, 1999; Lin et al, 2010; Terada et al, 2003; Villanueva et al, 2006; Witzgall et al, 1994). These coordinated responses are critical for nephron repair and recovery from AKI (Han et al, 2018)

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