Abstract: FR-PO341
TFEB Activation by Ceria-Zirconia Antioxidant Nanoparticles Attenuates Kidney Injury in Cellular and Animal Models of Fabry Disease
Session Information
- Genetic Diseases: Models, Mechanisms, Treatments
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Yoon, Se-Hee, Konyang University College of Medicine, Daejeon, Korea (the Republic of)
- Hwang, Won Min, Konyang University College of Medicine, Daejeon, Korea (the Republic of)
- Park, Yohan, Konyang University College of Medicine, Daejeon, Korea (the Republic of)
- Yun, Sung-Ro, Konyang University College of Medicine, Daejeon, Korea (the Republic of)
- Yoon, Kuk Ro, Hannam University, Daejeon, Korea (the Republic of)
Background
Fabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid-polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We investigated the signalling pathway of PEG-CZNPs associated with autophagy flux function and analyzed whether they suppress kidney injury in both cellular and animal models of FD.
Methods
PEG-CZNPs with size 2-3nm were synthesized using non-hydrolytic sol-gel reaction. HK-2 cells and conditionally human immortalized podocytes were transfected with shRNA targeting α-GLA. FD model mice, B6;129-Glatm1Kul/J (known as α-Gal A KO mice) were used for in-vivo study. Mice were sacrificed at 3- and 6-month age for investigation.
Results
PEG-CZNPs treatments decreased the intracellular globotriaosylceramide (Gb3) accumulation levels in both cellular and animal models of FD by enhancing the autophagy flux. PEG-CZNPs enhanced TFEB nuclear translocation by GSK3ß inhibition. Activated TFEB by PEG-CZNPs restored the blunted ATK/mTOR pathway in cellular models of FD. PEG-CZNPs leaded to decrease of the intracellular oxidative stress, inflammatory response and fibrosis in cellular and animal models of FD.
Conclusion
TFEB activation by PEG-CZNPs recovered the diminished autophagy flux function in cellular and animal models of FD and showed the potential as a new therapeutic medicine by alleviating the progression of kidney injury in FD.