First person – Lauren Brilli Skvarca and Hwa Han

摘要

First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Lauren Brilli Skvarca and Hwa Han are co-first authors on ‘ Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish ’, published in DMM. Lauren is a Pathologist Investigator Residency Research Training (PIRRT) Fellow at the University Pittsburgh Medical Center (UPMC), USA, in the lab of Carl Hubel, investigating maternal-fetal cell interactions contributing to placental vascular changes in preeclampsia and postpartum maternal cardiovascular risk. Hwa is a PhD graduate student in the lab of Neil Hukriede at the University of Pittsburgh School of Medicine, USA, and is involved in characterizing regenerative cellular mechanisms in gentamicin-induced acute kidney injury using larval zebrafish as a model organism. Hwa Han and Lauren Brilli Skvarca How would you explain the main findings of your paper to non-scientific family and friends? LBS+HH: The goal of our work is to understand how the kidney repairs itself after injury so that we can harness these innate mechanisms to develop better treatment options for people who experience acute kidney injury. This disease occurs more often in hospitalized patients than outpatients and has many causes, ranging from dehydration to infection. Drugs are another frequent cause of injury, although many of these drugs are necessary to treat serious conditions such as cancer or transplant rejection. These sometimes non-preventable causes of injury emphasize the need to find novel ways to enhance kidney regeneration. In our study, we used zebrafish to model acute kidney injury because its developing renal system harbors key similarities to the adult human kidney at the cellular level. We utilized zebrafish strains that allowed us to track multiple factors in the injury-repair pathway after delivery of PTBA, a compound that shows promise as a potential treatment for acute kidney injury. In kidney cells, we found that UPHD25 (PTBA prodrug) treatment reduced markers of injury and increased markers of repair. PTBA also altered the quantity and type of immune repair cells present in the kidney after injury. Our data suggest that these effects are mediated by retinoic acid signaling, a pathway known for its involvement in both organ development and regeneration in multiple contexts. This study provides insight into how PTBA works at the cellular level by identifying signaling pathways important for kidney repair. What are the potential implications of these results for your field of research? LBS+HH: We demonstrated that PTBA increases proliferation and dedifferentiation of proximal tubule cells in the zebrafish kidney. This complements previous work from our group and collaborators, which showed that PTBA increases renal function and ameliorates fibrosis in other kidney injury models, by delving deeper into the cellular mechanisms. Together, these results suggest that PTBA is a compelling candidate for further study. This is particularly important because no drugs are currently available to patients who experience acute kidney injury, so our work takes an exciting step toward expanding treatment options. However, much work is still required. Our current hypothesis is that PTBA acts as a histone deacetylase inhibitor, so our focus now is to identify target proteins and downstream pathways that may be critical in the pathophysiology of acute kidney injury. “Our work takes an exciting step toward expanding treatment options. However, much work is still required.” What are the main advantages and drawbacks of the model system you have used as it relates to the disease you are investigating? LBS: The pronephric larval zebrafish kidney is composed of only two nephrons. The simplicity of this system likely impairs the organism's ability to recover globally after kidney injury. So acute kidney injury is often fatal in our model, in contrast to mammals, which generally recover. However, this simplicity is also a strength. The entire renal system is contained within a small, optically clear organism that makes it ideally suited for time-lapse live imaging studies. For example, in our study, we performed live imaging in transgenic strains to track immune cells labeled with fluorescent proteins after kidney injury. This allowed us to characterize the immune cell milieu in proximity to each nephron and examine how the environment changed during the injury-repair sequence.