Abstract: TH-PO0594
Early Variable Gene of Alport Syndrome, Tnfsf15, Is a Protective Factor and Effect Modifier Against Renal Pathology
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Owaki, Aimi, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Kaseda, Shota, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Nishinakamura, Ryuichi, Department of Kidney Development, Institute of Developmental Medicine, Kumamoto University, Kumamoto, Japan
- Suico, Mary Ann, Department of Kidney Development, Institute of Developmental Medicine, Kumamoto University, Kumamoto, Japan
- Shuto, Tsuyoshi, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Kai, Hirofumi, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Background
Alport syndrome (AS) is a genetic disease of progressive glomerulonephritis caused by a mutation in type IV collagen. The progression of AS is irreversible, and it is important to control the progression of the disease by early therapeutic intervention. To know the early molecular changes, we performed single-cell RNA-seq (scRNA-seq) analysis in 5-week-old pre-proteinuric Col4a5 G5X AS mice and 8-week-old AS mice at the early stage of the disease.
Methods
Glomeruli from 5- and 8-week-old AS mice were collected using Dynabeads, processed for glomerular single cells, and sequenced. The scRNA-seq analysis revealed an early variable gene, Tnfsf15. To determine its function, we generated Tnfsf15 knockout (KO) AS mice and evaluated renal pathology.
Results
Glomerular scRNA-seq analysis revealed a marked change in podocyte gene expression. In particular, we focused on Tnfsf15, a gene whose expression was markedly increased at 5 and 8 weeks. The function of Tnfsf15 in AS is unclear, although it has been reported to be clinically associated with susceptibility to renal disease. Tnfsf15 KO AS mice had increased proteinuria, BUN, plasma creatinine, and decreased renal function compared to AS control. Glomerulosclerosis was exacerbated in Tnfsf15 KO AS mice. Some inflammation-related genes were up-regulated, but renal damage markers and fibrosis-related genes were unaltered in Tnfsf15 KO AS mice. In Tnfsf15 heterozygous AS mice, proteinuria and glomerulosclerosis were unchanged. However, Tnfsf15 expression significantly correlated with the genes related to renal injury, inflammation, and fibrosis, and the positive correlation slope was higher than the AS control. This suggests that Tnfsf15 is a modifier that affects the gene expression of pathology-related genes in Tnfsf15 heterozygous AS mice.
Conclusion
Tnfsf15, a podocyte-specific upregulated gene identified by scRNA-seq analysis, is suggested to be a protective factor and effect modifier of AS pathology.