Cyclosporine A blocks autophagic flux in tubular epithelial cells by impairing TFEB-mediated lysosomal function.
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.
['Li|Zhi-Hang|ZH|0000-0003-3621-7036', 'An|Ning|N|', 'Huang|Xi-Jie|XJ|', 'Yang|Chen|C|', 'Wu|Hong-Luan|HL|', 'Chen|Xiao-Cui|XC|', 'Pan|Qing-Jun|QJ|0000-0002-8060-9099', 'Liu|Hua-Feng|HF|']
D000818:Animals D001343:Autophagy D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors D016572:Cyclosporine D004847:Epithelial Cells D007166:Immunosuppressive Agents D007684:Kidney Tubules D008247:Lysosomes D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D058570:TOR Serine-Threonine Kinases
cyclosporine A tubular epithelial cells lysosome autophagy TFEB mTOR