Abstract: SA-PO0750
Integrative Multiomics and Spatial Profiling in Alport Syndrome
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 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
- Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
- Estevao, Igor L, Pacific Northwest National Laboratory, Richland, Washington, United States
- Gorman, Brittney L., Pacific Northwest National Laboratory, Richland, Washington, United States
- Sedrakyan, Sargis, Children's Hospital Los Angeles, Los Angeles, California, United States
- Clair, Geremy, Pacific Northwest National Laboratory, Richland, Washington, United States
Background
Alport Syndrome (AS) is characterized by interstitial fibrosis, glomerular basement membrane (GBM) disruption, and end-stage renal failure. While the genetic basis is known, the molecular and metabolic pathways underlying this disease are poorly understood. Here, we performed a kidney-level view linking metabolic, proteomic, lipidomic, and n-glycomic changes in AS.
Methods
We applied an integrated multi-omics approach using LC-MS/MS proteomics, lipidomics, metabolomics, and MALDI imaging MS for spatially resolved lipidomics, N-glycomics, and ECM proteins in kidneys from wild-type and Col4α5-KO mice.
Results
We identified 2,592 significantly altered proteins in Col4α5-KO kidneys. Striking abundance of interstitial and basement membrane-associated collagens, annexins, and integrin subunits (Fig.1) reflected ECM remodeling, suggesting maladaptive repair processes in response to GBM damage. Mitochondrial dysfunction emerged as a central signature of disease. We observed a broad decrease of mitochondrial ATP synthase components in AS (Fig.1), indicating metabolic imbalance and impaired energy metabolism. Reduced levels of NAD+, NADH, FAD, and NMN metabolites, and cardiolipins lipid species in AS (Fig.1), suggested compromised fatty acid oxidation and electron transport chain efficiency. Spatial lipidomics and glycomics further revealed regionalized alterations in lipid composition and ECM protein glycosylation patterns, underscoring tissue compartment-specific remodeling in AS kidneys.
Conclusion
This study presents the first integrative multi-omics and spatial biology atlas of AS, revealing a mechanistic connection between mitochondrial dysfunction and ECM remodeling. By capturing both tissue-specific and spatial molecular alterations, our work offers a high-resolution view of AS pathogenesis and valuable resources for identifying novel biomarkers for therapeutic intervention.
Funding
- NIDDK Support