Open AccessCyclosporine A blocks autophagic flux in tubular epithelial cells by impairing TFEB‐mediated lysosomal function
Author(s) -
Li Zhihang,
An Ning,
Huang Xijie,
Yang Chen,
Wu Hongluan,
Chen Xiaocui,
Pan Qingjun,
Liu Huafeng
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16593
Subject(s) - autophagy , tfeb , microbiology and biotechnology , pi3k/akt/mtor pathway , nephrotoxicity , cancer research , lysosome , flux (metallurgy) , pathogenesis , chemistry , biology , kidney , signal transduction , apoptosis , immunology , endocrinology , biochemistry , enzyme , organic chemistry
Cyclosporine A (CsA) is an immunosuppressor widely used for the prevention of acute rejection during solid organ transplantation. However, severe nephrotoxicity has substantially limited its long‐term usage. Recently, an impaired autophagy pathway was suggested to be involved in the pathogenesis of chronic CsA nephrotoxicity. However, the underlying mechanisms of CsA‐induced autophagy blockade in tubular cells remain unclear. In the present study, we observed that CsA suppressed the activation and expression of transcription factor EB (TFEB) by increasing the activation of mTOR, in turn promoting lysosomal dysfunction and autophagy flux blockade in tubular epithelial cells (TECs) in vivo and in vitro. Restoration of TFEB activation by Torin1‐mediated mTOR inhibition significantly improved lysosomal function and rescued autophagy pathway activity, suppressing TEC injury. In summary, targeting TFEB‐mediated autophagy flux represents a potential therapeutic strategy for CsA‐induced nephrotoxicity.