title: 4-Phenylbutyrate inhibits tunicamycin-induced acute kidney injury via CHOP/GADD153 repression.
abstract: Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA) is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s) of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP(-/-) mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression.
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Carlisle
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Brimble
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Werner
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Gaile L
authors.initials: GL
authors.lastname: Cruz
authors.affiliation: Department of Medicine, Division of Respirology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Ask
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
authors.affiliation: Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Dickhout
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010654:Phenylbutyrates / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014415:Tunicamycin / Q000009:adverse effects*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010654:Phenylbutyrates; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C075773:4-phenylbutyric acid