PUBLICATION
Delayed treatment with PTBA analogs reduces post injury renal fibrosis after kidney injury
- Authors
- Skrypnyk, N.I., Sanker, S., Brilli-Skvarca, L., Novitskaya, T., Woods, C., Chiba, T., Patel, K., Goldberg, N.D., McDermott, L., Vinson, P.N., Calcutt, M.W., Huryn, D.M., Vernetti, L.A., Vogt, A., Hukriede, N., de Caestecker, M.P.
- ID
- ZDB-PUB-151216-7
- Date
- 2016
- Source
- American journal of physiology. Renal physiology 310(8): F705-F71 (Journal)
- Registered Authors
- Chiba, Takuto, Hukriede, Neil
- Keywords
- Acute Kidney Injury, Drug Discovery, PTBA analogs, ischemia reperfusion and unilateral ureteric obstruction, zebrafish and mouse
- MeSH Terms
-
- Acute Kidney Injury/drug therapy*
- Acute Kidney Injury/pathology
- Animals
- Butyrates/pharmacology
- Butyrates/therapeutic use*
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Disease Models, Animal
- Fibrosis/drug therapy
- Fibrosis/pathology
- Kidney/drug effects*
- Kidney/pathology
- Male
- Mice
- Sulfides/pharmacology
- Sulfides/therapeutic use*
- Zebrafish
- PubMed
- 26661656 Full text @ Am. J. Physiol. Renal Physiol.
Citation
Skrypnyk, N.I., Sanker, S., Brilli-Skvarca, L., Novitskaya, T., Woods, C., Chiba, T., Patel, K., Goldberg, N.D., McDermott, L., Vinson, P.N., Calcutt, M.W., Huryn, D.M., Vernetti, L.A., Vogt, A., Hukriede, N., de Caestecker, M.P. (2016) Delayed treatment with PTBA analogs reduces post injury renal fibrosis after kidney injury. American journal of physiology. Renal physiology. 310(8):F705-F71.
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 post-injury repair in ischemia reperfusion and aristolochic acid induced AKI in mice. In these studies a new panel of PTBA analogs were 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 initiating injury.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping