Autophagic Inhibitor ROC-325 Ameliorates Glomerulosclerosis and Podocyte Injury via Inhibiting Autophagic Flux in Experimental FSGS Mice

Background: Podocyte-specific Yes-associated protein (YAP) deletion mice(YAP-KO mice), is considered a new animal model to study the underlying mechanism of FSGS. We sought to determine the therapeutic benefit of ROC-325, a novel small-molecule lysosomal autophagy inhibitor in FSGS model. Methods: Mass spectrometry were used to profile the downstream pathways in YAP-KO mice. Foot process morphology and autophagy level were detected by transmission electron microscopy. Immunofluorescence measured autophagy level and autophagic flux. Results: Mass spectrometry showed the processes linked to lysosome dysregulation have been significantly enrich in the YAP-KO mice. The results showed albuminuria, mesangial matrix expansion, and focal segmental glomerulosclerosis in YAP-KO mice were significantly attenuated by ROC-325. Corrugated capsule formation was greatly altered by ROC-325. Furthermore, ROC-325 treatment inhibited the autophagy activaty induced by YAP-KO by inhibiting autophagosome-lysosome fusion, and accumulation of LC3 and p62. Meanwhile, preapplication of ROC-325 in podocyte markedly suppressed autophagic flux. Conclusion: These results showed that the role of autophagic activity in FSGS and ROC-325 could be a promising agent for the treatment of FSGS. Funding: Government Support – Non-U.S.