PEG-Capped Ceria-Zirconia Nanoparticles Improved Renal Fibrosis in Cellular and Animal Models of Fabry Disease

Fabry disease (FD) is an X-linked hereditary disorder that results in the malfunction of alpha-galactosidase A (alpha GLA), leading to the accumulation of globotriaosylceramide (GB3) in cells and causing organ damage. This condition induces several pathological intracellular signaling pathways, with the dysfunction in autophagy being a crucial component. Phospholipid-polyethylene glycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. This study aims to assess the mechanisms of action of PEG-CZNPs in autophagy regulation and examine their effects on chronic kidney injury in cellular and animal models of FD. A stable cellular model of FD was successfully created through the shRNA transfection of alpha GLA. PEG-CZNPs were found to enhance autophagy flux by translocating Transcription factor EB (TFEB) to the nucleus. To demonstrate TFEB's importance in autophagy flux by PEG-CZNPs, HK-2 cells were transfected with siTFEB. Autophagy flux significantly decreased after the knockdown of TFEB, despite PEG-CZNPs treatment. We next assessed the upper signaling pathway of TFEB by PEG-CZNPs. TFEB dephosphorylation was significantly influenced by the Akt/GSK3 ss signaling pathway in response to PEG-CZNPs. PEG-CZNPs successfully reduced intracellular GB3 accumulation and decreased fibrous markers such as alpha-smooth muscle actin (alpha SMA), collagen type IV (ColIV), and matrix metallopeptidase 9 (MMP9) expression in the cellular model of FD. To evaluate the impact of PEG-CZNPs on kidney injury in a mouse model of FD, saline or PEG-CZNPs (10 mg/kg/day) were administered intraperitoneally twice per week for 24 or 48 weeks, starting at the age of 4 weeks. PEG-CZNPs significantly reduced both GB3 accumulation and alpha SMA expression in the kidneys. In conclusion, these results suggest that PEG-CZNPs promote autophagy flux through the Akt/GSK3 beta-TFEB signaling pathway and demonstrate a beneficial effect on kidney fibrosis and intracellular GB3 reduction in cellular and animal models of FD. These results provide valuable insights into potential therapeutics for FD.