Autophagy guards against cisplatin-induced acute kidney injury

Atsushi Takahashi, Tomonori Kimura, Yoshitsugu Takabatake, Tomoko Namba, Junya Kaimori, Harumi Kitamura, Isao Matsui, Fumio Niimura, Taiji Matsusaka, Naonobu Fujita, Tamotsu Yoshimori, Yoshitaka Isaka, Hiromi Rakugi

    Research output: Contribution to journalArticlepeer-review

    155 Citations (Scopus)

    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 proteinmicrotubule-associated protein 1 light chain 3) transgenic mice induced autophagy in kidney proximal tubules in a time-dependent manner. Proximal tubulespecific 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 speciesproducing 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.

    Original languageEnglish
    Pages (from-to)517-525
    Number of pages9
    JournalAmerican Journal of Pathology
    Volume180
    Issue number2
    DOIs
    Publication statusPublished - 2012 Feb

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine

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