ESCRT III-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.

Abstract

The chemotherapeutic agent cisplatin is widely utilized for the treatment of various solid tumors. However, its clinical utility is limited by nephrotoxicity. Although numerous studies have demonstrated the potential of enhancing macroautophagy/autophagy in alleviating cisplatin-induced acute kidney injury (AKI), the dynamics of the autophagic process during renal tubular injury remain to be elucidated. In our investigation, we observed that cisplatin treatment leads to increased expression of LC3-II, GABARAPL1, SQSTM1/p62 and NBR1 in mouse renal tubular epithelial cells and BUMPT cells. Moreover, ultrastructurally, there is extensive accumulation of autophagic vacuoles in AKI mice. These findings imply that cisplatin-induced AKI results in impaired autophagic flow within renal tubular cells. Furthermore, LGALS3 (galectin 3) was found to be enriched in lysosomes after cisplatin treatment, revealing a close association between autophagy dysfunction and impaired lysosomal membrane integrity. Given the damaging contents of lysosomes, lysosomal membrane permeabilization must be rapidly resolved. Our findings showed that ESCRT III subunit CHMP4A-mediated lysosomal membrane repair significantly ameliorates autophagic defects and protects against lysosomal damage-induced cell death in a cisplatin-induced AKI model. In conclusion, our study indicates that ESCRT III-mediated lysosomal repair can relieve cisplatin-induced cell apoptosis and restore normal autophagy function in renal tubular epithelial cells. This mechanism plays a protective role against cisplatin-induced AKI.Abbreviations: AAV: adeno-associated virus; AKI: acute kidney injury; CQ: chloroquine; ESCRT: endosomal sorting complex required for transport; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PAS: periodic acid Schiff; PTECs: proximal renal tubule epithelial cells; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.