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 α-galactosidase A (αGLA), 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 αGLA. 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/GSK3ß signaling pathway in response to PEG–CZNPs. PEG–CZNPs successfully reduced intracellular GB3 accumulation and decreased fibrous markers such as α-smooth muscle actin (αSMA), 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 αSMA expression in the kidneys. In conclusion, these results suggest that PEG–CZNPs promote autophagy flux through the Akt/GSK3β-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.