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Am J Physiol Renal Physiol. 2016 Apr 15;310(8):F705-F716. doi: 10.1152/ajprenal.00503.2015. Epub 2015 Dec 9.

Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.

Author information

1
Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
2
Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
4
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania;
5
Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee.
6
Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee.
7
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
8
Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
9
Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania.
10
Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee; mark.de.caestecker@vanderbilt.edu hukriede@pitt.edu.

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.

KEYWORDS:

PTBA analogs; acute kidney injury; drug discovery; phenotypic screening

PMID:
26661656
PMCID:
PMC4835925
DOI:
10.1152/ajprenal.00503.2015
[Indexed for MEDLINE]
Free PMC Article

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