| Authors |
Skrypnyk NI, Sanker S, Skvarca LB, Novitskaya T, Woods C, Chiba T, Patel K,
Goldberg ND, McDermott L, Vinson PN, Calcutt MW, Huryn DM, Vernetti LA, Vogt A,
Hukriede NA, de Caestecker MP
|
| Submitted By |
Mark P. de Caestecker on 7/3/2017 |
| Status |
Published |
| Journal |
American journal of physiology. Renal physiology |
| Year |
2016 |
| Date Published |
4/15/2016 |
| Volume : Pages |
310 : F705 - F716 |
| PubMed Reference |
26661656 |
| Abstract |
No therapies have been shown to accelerate recovery or prevent fibrosis after
acute kidney injury (AKI). In part, this is because most therapeutic candidates
have to be given at the time of injury and the diagnosis of AKI is usually made
too late for drugs to be efficacious. Strategies to enhance post-AKI repair
represent an attractive approach to address this. Using a phenotypic screen in
zebrafish, we identified 4-(phenylthio)butanoic acid (PTBA), which promotes
proliferation of embryonic kidney progenitor cells (EKPCs), and the PTBA methyl
ester UPHD25, which also increases postinjury repair in ischemia-reperfusion and
aristolochic acid-induced AKI in mice. In these studies, a new panel of PTBA
analogs was evaluated. Initial screening was performed in zebrafish EKPC assays
followed by survival assays in a gentamicin-induced AKI larvae zebrafish model.
Using this approach, we identified UPHD186, which in contrast to UPHD25,
accelerates recovery and reduces fibrosis when administered several days after
ischemia-reperfusion AKI and reduces fibrosis after unilateral ureteric
obstruction in mice. UPHD25 and 186 are efficiently metabolized to the active
analog PTBA in liver and kidney microsome assays, indicating both compounds may
act as PTBA prodrugs in vivo. UPHD186 persists longer in the circulation than
UPHD25, suggesting that sustained levels of UPHD186 may increase efficacy by
acting as a reservoir for renal metabolism to PTBA. These findings validate use
of zebrafish EKPC and AKI assays as a drug discovery strategy for molecules that
reduce fibrosis in multiple AKI models and can be administered days after
initiation of injury.
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