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

• DOI: 10.1242/dmm.037390
• Publication Date: 2019-04-05T13:57:19Z
• Authors: Lauren Brilli Skv...; 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
• Keywords: 0301 basic medicine; Neutrophils; Renal proximal tubule cell; Tretinoin; Sulfides; Cardiovascular; Animals, Genetically Modified; 03 medical and health sciences; HDAC inhibitor; Pathology; RB1-214; Animals; Regeneration; Prodrugs; Zebrafish; Cell Proliferation; Macrophages; PAX2 Transcription Factor; R; Epithelial Cells; Acute Kidney Injury; Cell Dedifferentiation; Zebrafish Proteins; Acute kidney injury; Butyrates; Kidney Tubules; Immune System; Medicine; Therapeutic; Research Article; Signal Transduction

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