title: Autophagy guards against cisplatin-induced acute kidney injury.
abstract: Autophagy is a highly conserved bulk protein degradation pathway involved in cellular homeostasis. Although emerging evidence indicates involvement of autophagy in various conditions, efforts to clarify the role of autophagy in renal tubules are beginning to be elucidated. In the present study, we examined the hypothesis that autophagy guards against acute kidney injury (AKI) by modulating several deteriorative pathways that lead to tubular cell death using a cisplatin-induced model of AKI. Cisplatin treatment of GFP-LC3 (green fluorescent protein-microtubule-associated protein 1 light chain 3) transgenic mice induced autophagy in kidney proximal tubules in a time-dependent manner. Proximal tubule-specific autophagy-deficient mice exhibited more severe cisplatin-induced AKI than did control mice, as assessed via kidney function and morphologic findings. In addition, cisplatin induced more severe DNA damage and p53 activation, concomitant with an increase in apoptotic cell number, and a massive accumulation of protein aggregates in autophagy-deficient proximal tubules. Cisplatin treatment significantly increased reactive oxygen species-producing damaged mitochondria in immortalized autophagy-deficient proximal tubular cells when compared with autophagy-retrieved control cells. In conclusion, autophagy guards kidney proximal tubules against AKI, possibly by alleviating DNA damage and reactive oxygen species production and by eliminating toxic protein aggregates. Enhancing autophagy may provide a novel therapeutic option to minimize AKI.
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.forename: Tomoko
authors.initials: T
authors.lastname: Namba
authors.forename: Junya
authors.initials: J
authors.lastname: Kaimori
authors.forename: Harumi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.forename: Fumio
authors.initials: F
authors.lastname: Niimura
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: Naonobu
authors.initials: N
authors.lastname: Fujita
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C490981:Gtf2h1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D051758:Transcription Factor TFIIH; D002945:Cisplatin