Abstract: TH-PO0585
ADAMTS13 Protects Kidney Function in Alport Syndrome
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
- Soloyan, Hasmik, Children's Hospital Los Angeles, Los Angeles, California, United States
- Chomoyan, Hripsime, Children's Hospital Los Angeles, Los Angeles, California, United States
- Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Perin, Laura, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Sedrakyan, Sargis, University of Southern California Keck School of Medicine, Los Angeles, California, United States
Background
Alport syndrome (AS) is a hereditary form of CKD caused by mutations in type IV collagen genes, leading to progressive renal failure. Despite advances in understanding its genetic basis, effective treatments to slow disease progression remain limited. Our research has shown that glomerular endothelial cells (GECs) are among the first to be damaged in AS and intravital imaging studies revealed that glomerular capillaries in AS mice are affected by microthrombi formations. We have previously shown that ADAMTS13, an enzyme responsible for cleaving von Willebrand factor (VWF) is consistently downregulated in human kidney biopsies affected by AS. This study investigates if disrupted fatty acid metabolism drives the downregulation of ADAMTS13, and whether ADAMTS13 administration in AS mice can protect glomerular microvasculature and slow down disease progression.
Methods
In vitro, silencing experiments on primary human GEC were performed to study the role of fatty acid metabolism on ADAMTS13 expression. In vivo, Col4a5-KO Alport mice were treated with bi-weekly administration of recombinant ADAMTS13 protein and kidney function was assessed.
Results
We established that glomerular ADAMTS13 expression is downregulated in Col4a5-KO Alport mice with moderate disease. Our analysis revealed that suppression of fatty acid synthesis downregulates ADAMTS13 expression in GECs. Knockdown of ADAMTS13 in GECs led to endothelial dysfunction, indicated by increased levels of the adhesion molecules VCAM-1 and ICAM-1. Notably, therapeutic administration of ADAMTS13 in Alport mice resulted in significant improvement in proteinuria.
Conclusion
Our findings reveal that endothelial metabolic dysfunction and ADAMTS13 downregulation contribute to microvascular injury and endothelial dysfunction in AS. These results suggest that ADAMTS13 restoration may serve as a promising therapeutic strategy to preserve endothelial function and slow CKD progression in AS, and potentially other forms of CKD.
Funding
- NIDDK Support