International immunopharmacology · 2026
TFEB has a protective effect in cisplatin induced AKI through regulating exosome-MVBs pathway.
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Xu Zhifeng, Xiang Huiling, Liu Huixia, Zhang Chun, Zhang Xiaoli, Xiong Jing
Аннотация
BACKGROUND: Acute kidney injury (AKI) is characterized by a rapid decline in renal function and is associated with high mortality worldwide. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, exerts protective effects in AKI, although the underlying mechanisms remain unclear. Exosomes derived from multivesicular bodies (MVBs) play diverse roles in kidney diseases. Emerging evidence suggests that lysosome-dependent degradation of MVBs plays an important role in regulating exosome secretion. Based on this, TFEB may inhibit exosome secretion by promoting lysosomal biogenesis and lysosome-dependent degradation of MVBs, thereby attenuating AKI progression.
METHODS: In this study, rat renal tubular epithelial cells (TECs) were treated with cisplatin under TFEB modulation (TFEB siRNA or trehalose), to assess TFEB expression, lysosome-related molecules, exosome secretion, and MVBs dynamics. In vivo, TFEB-overexpressing lentivirus was injected into mouse kidneys followed by cisplatin-induced AKI, and changes in TFEB, lysosomal function, and the MVB-exosome pathway were evaluated.
RESULTS: Our results showed that cisplatin promoted the release of pathogenic exosomes from TECs, which in turn damaged neighboring healthy TECs via paracrine effects. In rat TECs, trehalose-induced TFEB upregulation enhanced lysosomal biogenesis and MVB degradation, thereby reducing cisplatin-induced exosome secretion and TEC injury. Similarly, in cisplatin-induced AKI mice, TFEB overexpression alleviated renal damage. Exosome secretion was increased in AKI mice, but this increase was attenuated in mice injected with a TFEB-overexpressing lentivirus. TFEB overexpression led to increased cathepsin D (CTSD) expression, decreased expression of MVB-related proteins, and significantly enhanced MVB-lysosome interaction.
CONCLUSION: Cisplatin-induced exosome secretion from TECs promotes injury in neighboring TECs. TFEB protects against cisplatin-induced AKI by enhancing lysosome-dependent degradation of MVBs, thereby reducing pathogenic exosome secretion from TECs and alleviating kidney damage.
METHODS: In this study, rat renal tubular epithelial cells (TECs) were treated with cisplatin under TFEB modulation (TFEB siRNA or trehalose), to assess TFEB expression, lysosome-related molecules, exosome secretion, and MVBs dynamics. In vivo, TFEB-overexpressing lentivirus was injected into mouse kidneys followed by cisplatin-induced AKI, and changes in TFEB, lysosomal function, and the MVB-exosome pathway were evaluated.
RESULTS: Our results showed that cisplatin promoted the release of pathogenic exosomes from TECs, which in turn damaged neighboring healthy TECs via paracrine effects. In rat TECs, trehalose-induced TFEB upregulation enhanced lysosomal biogenesis and MVB degradation, thereby reducing cisplatin-induced exosome secretion and TEC injury. Similarly, in cisplatin-induced AKI mice, TFEB overexpression alleviated renal damage. Exosome secretion was increased in AKI mice, but this increase was attenuated in mice injected with a TFEB-overexpressing lentivirus. TFEB overexpression led to increased cathepsin D (CTSD) expression, decreased expression of MVB-related proteins, and significantly enhanced MVB-lysosome interaction.
CONCLUSION: Cisplatin-induced exosome secretion from TECs promotes injury in neighboring TECs. TFEB protects against cisplatin-induced AKI by enhancing lysosome-dependent degradation of MVBs, thereby reducing pathogenic exosome secretion from TECs and alleviating kidney damage.