Department of Developmental Biology
3501 Fifth Avenue
Pittsburgh, Pennsylvania 15260
Acute kidney injury (AKI) is associated with a high mortality and morbidity and AKI survivors often develop end stage renal disease. At present, there are no established therapies to prevent renal injury or accelerate the rate of renal recovery following AKI. The consequences of abnormal kidney function are frequently fatal, with dialysis and organ transplantation the only current long-term treatments for kidney disease. Importantly, the vertebrate kidney has the potential to regenerate, but the molecular mechanisms of kidney regeneration are largely unknown. A better understanding of the processes controlling renal repair after injury may provide important clues for the development of new therapies for the treatment of degenerative kidney diseases. The Hukriede lab focuses on two lines of study. (1) To explore the link between mechanisms of kidney regeneration and organogenesis they examine damaged kidneys in vivo. Using zebrafish transgenic lines such as lhx1a:eGFP, pax2a:GFP, NakATPase:tdTomato, and chd17:mCherry reactivation of embryonic kidney genes in larval and adult AKI models can be analyzed by real-time image analysis. Interestingly, the signaling pathways reactivated during kidney regeneration are similar to those involved in kidney organogenesis. (2) The Hukriede lab performs chemical screens to identify compounds that could increase the number of renal progenitor cells. A compound identified from one such screen, 4-(phenylthio)butanoic acid (PTBA), expanded the expression domains of molecular markers of kidney organogenesis. PTBA exhibits structural and functional similarity to histone deacetylase inhibitors (HDACi). Accordingly, in vitro and in vivo analysis confirmed that PTBA functions as a new HDACi. Furthermore, studies on PTBA-mediated kidney regeneration have shown drug treatments increase the rate of renal recovery and decrease fibrosis. These findings validate our strategy that discoveries using the zebrafish model are directly translatable to mammalian models of AKI. We are currently focusing on identifying additional analogues that display increased efficacy with reduced toxicity compared with the parent compound in the hope that treatment with this class of HDACi will confer a therapeutic benefit to patients suffering from AKI.
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