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4-Phenylthiobutanoic Acid Inhibits Histone Deacetylase 8 to Enhance Post-Acute Kidney Injury Repair

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4-Phenylthiobutanoic Acid Inhibits Histone Deacetylase 8 to Enhance Post-Acute Kidney Injury Repair Title Page Slow and Steady: 4-Phenylthiobutanoic Acid Inhibits Histone Deacetylase 8 to Enhance Post-Acute Kidney Injury Repair by Hwa In Han B.S., College of William & Mary, 2014 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2020 Committee Page UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Hwa In Han It was defended on May 29, 2020 and approved by Jacqueline Ho, M.D., Department of Pediatric Nephrology Penelope Morel, M.D., Department of Immunology Kyle Orwig, Ph.D., Department of Obstetrics, Gynecology & Reproductive Services Michael Tsang, Ph.D., Department of Developmental Biology Dissertation Director: Neil Hukriede, Ph.D., Department of Developmental Biology ii Copyright © by Hwa In Han 2020 iii Abstract Slow and Steady: 4-Phenylthiobutanoic Acid Inhibits Histone Deacetylase 8 to Enhance Post-Acute Kidney Injury Repair Hwa In Han, PhD University of Pittsburgh, 2020 Acute kidney injury (AKI) is a rapid decline in kidney function that is associated with high mortality and morbidity rates, affecting 1 in 5 adults worldwide 1. While damaged renal tubular epithelial cells (RTECs) undergo reparative process to proliferate and replace the damaged epithelium, it is not a robust mechanism. The initial damage is followed by a cross-talk of innate immune system and RTECs resulting in exacerbation of inflammation, fibrosis, and sometimes irreversible damage. Despite the prevalence and severity of AKI, no FDA approved therapeutics exist to replace damaged or lost RTECS. Therefore, it is imperative to screen, identify, and understand mechanisms with which candidate therapeutics can enhance repair. Our group identified 4-phenylthiobutanoic acid (PTBA) and developed analogs to enhance renal repair when treated post-AKI. However, the protein target(s) as well as the mechanisms responsible for enhanced recovery are not completely understood. Here, we used a zebrafish larvae AKI model to visualize RTEC cellular response during PTBA treatment. We also characterized the zebrafish immune response during AKI and the effect of PTBA on modulating the innate immune cell response. Lastly, we used in vivo and in vitro methods to identify the target of PTBA, Histone deacetylase 8 (HDAC8). Using knockout hdac8 (hdac8-/-) zebrafish, we showed a similarly enhanced recovery of hdac8-/- as we saw in animals treated with PTBA. We further demonstrated the hdac8-/- show changes cell cycle dynamics and epithelial to mesenchymal transition. Taken together, our work provides another step forward in pro-regenerative compound development. iv Table of Contents Preface ......................................................................................................................................... xiii 1.0 Background ............................................................................................................................. 1 1.1 Kidney development, structure, and function ............................................................. 1 1.1.1 Mammalian kidney development........................................................................1 1.1.2 Zebrafish kidney development ............................................................................3 1.1.3 Nephron segmentation .........................................................................................5 1.2 Acute kidney injury ........................................................................................................ 7 1.2.1 Definition, epidemiology, and classification ......................................................7 1.2.2 Risks and treatment .............................................................................................8 1.2.3 Cellular pathophysiology .....................................................................................9 1.2.3.1 Epithelial component ............................................................................. 10 1.2.3.2 Adaptive Repair ..................................................................................... 11 1.2.3.3 Maladaptive repair ................................................................................ 12 1.3 Cell cycle behavior during AKI ................................................................................... 14 1.3.1 Cell cycle components ........................................................................................14 1.3.2 RTEC cell cycle under injury ...........................................................................17 1.4 Innate immune system activation in AKI ................................................................... 20 1.4.1 Macrophages .......................................................................................................20 1.4.1.1 Origin and function ............................................................................... 20 1.4.1.2 Activation during AKI .......................................................................... 22 1.4.1.3 Macrophage polarization ...................................................................... 24 v 1.4.2 Neutrophils .........................................................................................................26 1.4.2.1 Origin and function ............................................................................... 26 1.4.2.2 Activation in AKI ................................................................................... 27 1.5 Zebrafish as model organism ...................................................................................... 31 1.5.1 General strengths of zebrafish ..........................................................................31 1.5.2 Larval zebrafish model of AKI .........................................................................32 1.5.2.1 Development recapitulation during injury .......................................... 33 1.5.3 Zebrafish as model organism to study innate immune response ...................35 1.6 4-phenylthiobutanoic acid (PTBA) ............................................................................. 36 1.6.1 Origins of PTBA .................................................................................................36 1.6.2 PTBA treatment in AKI ....................................................................................37 1.7 Histone deacetylase 8 .................................................................................................... 39 1.7.1 General knowledge .............................................................................................39 1.7.2 HDAC8 in development and disease ................................................................40 1.7.3 HDAC8 in cell cycle and beyond ......................................................................42 2.0 Elucidating mechanisms of PTBA in enhancing post-AKI recovery ............................... 47 2.1 Hypothesis ..................................................................................................................... 47 2.2 Results ............................................................................................................................ 48 2.2.1 PTBA increases dedifferentiation and proliferation post-AKI ......................48 2.2.2 PTBA increases dedifferentiation and ameliorates injury .............................50 2.2.3 Intact retinoic acid signaling pathway is required for PTBA efficacy ..........53 2.3 Methods ......................................................................................................................... 58 2.3.1 Zebrafish husbandry ..........................................................................................58 vi 2.3.2 Gentamicin microinjection ................................................................................58 2.3.3 Compound treatment .........................................................................................59 2.3.4 Heat shock treatment .........................................................................................59 2.3.5 Histological Analysis ..........................................................................................60 2.3.6 RNA isolation of zebrafish pronephros ............................................................60 2.3.7 cDNA library preparation and RNA sequencing ............................................61 2.3.8 Statistical analysis ..............................................................................................61 2.4 Discussion ...................................................................................................................... 61 3.0 Characterizing innate immune system activation in larval zebrafish acute kidney injury ............................................................................................................................................ 65 3.1 Hypothesis ..................................................................................................................... 65 3.2 Results ............................................................................................................................ 66 3.2.1 Larval zebrafish AKI activates neutrophil migration ....................................66 3.2.2 Larval zebrafish AKI activates macrophage migration .................................67 3.2.3 PTBA treatment decreases macrophage migration ........................................70 3.2.4 PTBA treatment affects macrophage polarization .........................................72
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