Abstract: FR-PO0792
Heterozygous Col4a3 Mutation Increases Susceptibility to Doxorubicin-Induced Podocytopathy
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Miyata, Kana, Saint Louis University School of Medicine, St. Louis, Missouri, United States
- Smith, Denise, Saint Louis University School of Medicine, St. Louis, Missouri, United States
- Yamashita, Michifumi, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Kim, Shimok, Saint Louis University School of Medicine, St. Louis, Missouri, United States
- Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Miner, Jeffrey H., Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
- Bruno, Jonathan M., Saint Louis University School of Medicine, St. Louis, Missouri, United States
Background
Podocyte injury and loss are key initiating events in Focal segmental glomerulosclerosis (FSGS) development. While COL4A3 and COL4A4 variants were once linked to benign thin basement membrane nephropathy, they are now recognized as the most frequent genetic causes of adult-onset FSGS. The mechanisms linking COL4-related glomerular basement membrane (GBM) defects to podocyte injury remain poorly understood.
Methods
To assess the impact of Col4a3 mutations on susceptibility to podocyte injury, we induced podocytopathy by administering intravenous doxorubicin (Dox; 8 mg/kg) to wild-type (WT; Col4a3+/+) and heterozygous (HET; Col4a3+/-) male mice on a 129S1/SvImJ background. Their littermates that received saline served as controls. Dox or saline were administered at 6 weeks of age, and mice were euthanized at 10 weeks of age. Urine and blood samples were collected for biochemical analysis, and kidney tissues were examined histologically.
Results
HET mice with saline injection showed no significant differences in the urinary albumin-creatinine ratio (UACR), blood urea nitrogen, or histological features compared to WT mice with saline injection. HET mice with Dox exhibited a significantly higher UACR than WT mice with Dox, while there was no difference in body weight, kidney weight, or BUN between the two groups. In addition, HET mice with Dox had increased glomerulosclerosis score (PAS staining) and greater tubulointerstitial fibrosis (Sirius red staining) compared to WT mice with Dox.
Conclusion
Heterozygous Col4a3 mutations increase susceptibility to Dox-induced podocytopathy. These findings support a pathogenic role for GBM abnormalities in the development of FSGS. Ongoing studies aim to elucidate the underlying molecular mechanisms.