Abstract: TH-PO0592
From Filter to Failure: Serpin-Driven Glomerulotubular Injury 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
- Da Sacco, Stefano, Children's Hospital Los Angeles, Los Angeles, California, United States
- Kasravi, Mohammadreza, Children's Hospital Los Angeles, Los Angeles, California, United States
- Sedrakyan, Sargis, Children's Hospital Los Angeles, Los Angeles, California, United States
- Gyarmati, Georgina, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Peti-Peterdi, Janos, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
Background
Alport Syndrome (AS) is a hereditary CKD marked by progressive glomerular damage and loss of glomerular filtration barrier (GFB) integrity, leading to proteinuria and renal failure. Despite the well-established role of GFB damage in the AS pathogenesis, the mechanistic link between GFB dysfunction and tubular alterations remains unclear. Serpins, particularly serpin A3, contribute to endothelial dysfunction, inflammation, and extracellular matrix remodeling, potentially exacerbating glomerular injury and inducing secondary tubular damage. By deciphering the role of these proteins, we hope to uncover novel therapeutic strategies for AS patients.
Methods
This study utilized a novel nephron-on-a-chip (NOAC) model, integrating glomerulus-on-a-chip (GOAC) and proximal tubule-on-a-chip (PTOAC) to investigate AS mechanisms. KIM-1 levels in NOAC filtrates indicated tubular injury following serpin A3 exposure. GEC alterations were assessed using intravital multiphoton microscopy (MPM) in AS mouse kidneys, while proteomic analysis of AS-GOAC filtrates identified dysregulated proteins. Digital Spatial Profiling (DSP) further validated gene expression changes in human AS glomeruli.
Results
MPM imaging of AS mice revealed severe glomerular endothelial alterations, including capillary dilation, aneurysms, microthrombi, and increased albumin leakage. Proteomic analysis of AS-GOAC filtrates identified elevated serpin A3, a marker of glomerular damage, while DSP confirmed gene expression changes in human AS glomeruli, affecting GEC function and serpin dysregulation. Additionally, increased KIM-1 expression in PTOAC filtrates following serpin A3 treatment suggests a detrimental effect on proximal tubular cells.
Conclusion
Our findings suggest that increased expression of serpins, particularly serpin A3, contributes to GEC dysfunction and negatively impacts the tubular compartment, further disrupting nephron homeostasis. Ongoing studies utilizing GOACs generated with healthy and AS human AKPCs will further elucidate the role of serpin dysregulation in AS pathogenesis. Additionally, NOAC-based assessments will provide insights into how these alterations affect proximal tubular cells, potentially identifying new therapeutic targets for AS-associated CKD progression.
Funding
- Private Foundation Support