title: Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Nataliya I
authors.initials: NI
authors.lastname: Skrypnyk
authors.affiliation: Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sanker
authors.affiliation: Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lauren Brilli
authors.initials: LB
authors.lastname: Skvarca
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novitskaya
authors.affiliation: Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Clara
authors.initials: C
authors.lastname: Woods
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.|Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Takuto
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kevin
authors.initials: K
authors.lastname: Patel
authors.affiliation: Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Natasha D
authors.initials: ND
authors.lastname: Goldberg
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Lee
authors.initials: L
authors.lastname: McDermott
authors.affiliation: Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.affiliation: Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: M Wade
authors.initials: MW
authors.lastname: Calcutt
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.affiliation: Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Vernetti
authors.affiliation: Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hukriede
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee; mark.de.caestecker@vanderbilt.edu hukriede@pitt.edu.|Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use*; D015027:Zebrafish
chemical_list: C549619:4-(phenylthio)butanoic acid; D002087:Butyrates; D013440:Sulfides
keywords: PTBA analogs; acute kidney injury; drug discovery; phenotypic screening