title: Histone deacetylase inhibitor enhances recovery after AKI.
abstract: At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought to identify candidate compounds that accelerate recovery after AKI by screening for small molecules that increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from this screen was the histone deacetylase inhibitor methyl-4-(phenylthio)butanoate, which we subsequently administered to zebrafish larvae and mice 24-48 hours after inducing AKI. In zebrafish, treatment with the compound increased larval survival and proliferation of renal tubular epithelial cells. In mice, treatment accelerated recovery, reduced postinjury tubular atrophy and interstitial fibrosis, and increased the regenerative capacity of actively cycling renal tubular cells by decreasing the number of cells in G2/M arrest. These data suggest that accelerating recovery may be a viable approach to treating AKI and provide proof of concept that a screen in zebrafish embryos can identify therapeutic candidates for kidney injury.
authors.affiliation: Department of Developmental Biology, University of Pittsburgh, Pittsburgh,PA, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cianciolo Cosentino
authors.forename: Nataliya I
authors.initials: NI
authors.lastname: Skrypnyk
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Brilli
authors.forename: Takuto
authors.initials: T
authors.lastname: Chiba
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novitskaya
authors.forename: Clara
authors.initials: C
authors.lastname: Woods
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Vasiliy N
authors.initials: VN
authors.lastname: Korotchenko
authors.forename: Lee
authors.initials: L
authors.lastname: McDermott
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Davidson
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hukriede
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D005839:Gentamicins / Q000633:toxicity; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010654:Phenylbutyrates / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D020127:Recovery of Function / Q000187:drug effects; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D005839:Gentamicins; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D011500:Protein Synthesis Inhibitors; D029961:Zebrafish Proteins; C582715:methyl-4-(phenylthio)butanoate; C488363:HDAC1 protein, zebrafish; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1