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Developing Pro-regenerative Drug Therapies for Acute Kidney Injury

Key Personnel

Neil Hukriede (PI)
University of Pittsburgh

Alan Davidson (PI)
University of Auckland

Project Description

Acute kidney injury (AKI) is a major health problem and there are currently no effective treatments. We have identified a novel class of compounds (PTBA) that reduce AKI injury when administered days after the initiating injury. However, how PTBA prevents kidney injury remains unclear. Our goal is to use human kidney organoids generated from induced pluripotent stem cells (iPSCs) as a tool to understand the pro-regenerative mechanism-of-action of PTBA analogs during kidney injury and repair, and to further validate the kidney organoid system as a pre-clinical drug screening platform.

Publications

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

    Brilli Skvarca, Lauren; Han, Hwa In; Espiritu, Eugenel B.; Missinato, Maria A.; Rochon, Elizabeth R.; McDaniels, Michael D.; Bais, Abha S.; Roman, Beth L.; Waxman, Joshua S.; Watkins, Simon C.; Davidson, Alan J.; Tsang, Michael; Hukriede, Neil A. Dis Model Mech. 12(4). April 2019.

    Acute 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

  2. Wnt signaling mediates new nephron formation during zebrafish kidney regeneration

    Kamei, Caramai N.; Gallegos, Thomas F.; Liu, Yan; Hukriede, Neil; Drummond, Iain A. Development. 146(8). April 2019.

    Zebrafish kidneys use resident kidney stem cells to replace damaged tubules with new nephrons: the filtration units of the kidney. What stimulates kidney progenitor cells to form new nephrons is not known. Here, we show that wnt9a and wnt9b are induced in the injured kidney at sites where frizzled9b- and lef1-expressing progenitor cells form new nephrons. New nephron aggregates are patterned by Wnt signaling, with high canonical Wnt-signaling cells forming a single cell thick rosette that demarcates: domains of cell proliferation in the elongating nephron; and tubule fusion where the new nephron plumbs into the distal tubule and establishes blood filtrate drainage. Pharmacological blockade of canonical Wnt signaling inhibited new nephron formation after injury by inhibiting cell proliferation, and resulted in loss of polarized rosette structures in the aggregates. Mutation in frizzled9b reduced total kidney nephron number, caused defects in tubule morphology and reduced regeneration of new nephrons after injury. Our results demonstrate an essential role for Wnt/frizzled signaling in adult zebrafish kidney development and regeneration, highlighting conserved mechanisms underlying both mammalian kidney development and kidney stem cell-directed neonephrogenesis in zebrafish.

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

    Brilli Skvarca, Lauren; Han, Hwa In; Espiritu, Eugenel B.; Missinato, Maria A.; Rochon, Elizabeth R.; McDaniels, Michael D.; Bais, Abha S.; Roman, Beth L.; Waxman, Joshua S.; Watkins, Simon C.; Davidson, Alan J.; Tsang, Michael; Hukriede, Neil A. Dis Model Mech. 12(4). April 2019.

    Acute 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