Human kidney organoids reveal the role of glutathione in Fabry disease

Fabry disease: organoid model suggests possible antioxidant treatment Kidney organoids harboring the gene mutation that causes Fabry disease provide valuable models for the condition and could inform treatment pathways. Fabry disease is a rare inherited disorder caused by a mutation in the gene for the enzyme galactosidase alpha (GLA). This triggers a build-up of a specific type of fat within cells, which impairs cellular functioning and can cause life-threatening complications. Young Kyun Kim and co-workers at the Catholic University of Korea, Seoul, used human inducible pluripotent stem cells to create kidney organoids with the GLA mutation. Analysis of the organoids revealed deformed epithelial tubular cells and podocytes with dense fat-like deposits inside their cytoplasm. The organoids exhibited high oxidative stress levels, and decreased metabolism of the natural antioxidant, glutathione. The team found that boosting glutathione improved the organoids' cellular structures and decreased oxidative stress. Fabry disease is an X-linked lysosomal storage disease caused by a mutation in the galactosidase alpha (GLA) gene. Despite advances in therapeutic technologies, the lack of humanized experimental models of Fabry disease has limited the development of new therapies to cure the disease. Herein, we modeled Fabry disease using human inducible pluripotent stem cell (iPSC)-derived kidney organoids and the CRISPR-Cas9 genome-editing system. GLA-mutant human kidney organoids revealed deformed podocytes and tubular cells with accumulation of globotriaosylceramide (Gb3). Ultrastructural analysis showed abundant electron-dense granular deposits and electron-dense lamellate lipid-like deposits that formed concentric bodies (zebra bodies) in the cytoplasm of podocytes and tubules. The oxidative stress level was increased in GLA-mutant kidney organoids, and the increase was accompanied by apoptosis. Enzyme replacement treatment (ERT) with recombinant human alpha-Gal A decreased the Gb3 accumulation and oxidative stress, which resulted in amelioration of the deformed cellular structure of the GLA-mutant kidney organoids. Transcription profile analyses showed decreased glutathione (GSH) metabolism in GLA-mutant kidney organoids. GSH replacement treatment decreased oxidative stress and attenuated the structural deformity of the GLA-mutant kidney organoids. GSH treatment also increased the expression of podocyte and tubular markers and decreased apoptosis. In conclusion, GLA-mutant kidney organoids derived from human iPSCs are valuable tools for studying the mechanisms and developing novel therapeutic alternatives for Fabry disease.

Automated summary

Fabry disease is a rare inherited disorder caused by a mutation in the GLA gene, leading to the accumulation of fat in cells and causing severe complications. By using kidney organoids with the GLA mutation, researchers found high oxidative stress levels and decreased metabolism of the antioxidant glutathione. Boosting glutathione improved cellular structures and reduced oxidative stress in the organoids.