TFEB Mitigates Cisplatin-Induced AKI by Promoting Lysosomal Degradation of Multivesicular Bodies and Reducing Exosome Release

Background: Acute kidney injury (AKI) causes rapid renal function decline and high mortality worldwide. Transcription factor EB (TFEB) has renal protective effects in AKI, but its mechanism remains unclear. Exosomes released from multivesicular bodies (MVBs) participate in kidney disease progression. TFEB may regulate MVB-exosome secretion by promoting lysosome biogenesis, influencing AKI development. Methods: Rat renal tubular epithelial cells (TECs) were treated with cisplatin. Levels of TFEB, lysosome-related proteins, exosome secretion, and MVB expression were measured. In vivo, TFEB-overexpressing lentivirus was injected into mouse kidneys, followed by cisplatin-induced AKI. Changes in TFEB, lysosome markers, and the exosome-MVB pathway were analyzed. Results: Cisplatin stimulated TECs to release exosomes containing harmful cargo, damaging neighboring healthy TECs via paracrine effects. Trehalose-induced TFEB activation in rat TECs enhanced lysosome biogenesis and promoted MVB degradation, reducing cisplatin-induced exosome secretion and cell injury. In AKI mice, TFEB overexpression mitigated renal damage and decreased exosome marker expression. TFEB upregulation increased cathepsin D (CTSD), decreased MVB-associated proteins, and enhanced MVB-lysosome fusion. Conclusion: Cisplatin-induced exosome secretion from TECs contributes to AKI progression by injuring adjacent cells. TFEB protects against cisplatin-induced AKI by promoting lysosomal degradation of MVBs, reducing harmful exosome release and renal injury. Funding: Government Support – Non-U.S.