Abstract: FR-PO785
Murine Model of Glomerular Thrombotic Microangiopathy Results in Glomerular Endothelial-to-Mesenchymal Transition
Session Information
- Glomerular Diseases: Mechanisms and Podocyte Biology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Droste, Patrick, Institute of Pathology, University Hospital RWTH Aachen,, Aachen, Germany
- Djudjaj, Sonja, Institute of Pathology, University Hospital RWTH Aachen,, Aachen, Germany
- Klinkhammer, Barbara Mara, Institute of Pathology, University Hospital RWTH Aachen,, Aachen, Germany
- Buhl, Eva Miriam, Institute of Pathology, University Hospital RWTH Aachen,, Aachen, Germany
- Kemter, Elisabeth, Institute of Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, München, Germany
- Boor, Peter, Institute of Pathology, University Hospital RWTH Aachen,, Aachen, Germany
Group or Team Name
- Laboratory of Nephropathology.
Background
Thrombotic microangiopathies (TMAs) are rare diseases with a poor prognosis and a multifaceted manifestation pattern. The pathological processes in the glomerulus during TMA are incompletely understood, also because very few animal models are available. Here, we characterized a murine model with glomerular-limited endothelial cell injury with thrombi.
Methods
Eight-week-old healthy wild-type littermate mice were compared with mutated diseased mice (generated by random mutagenesis). Perfused kidneys were investigated with histological, immunohistochemical, and immunofluorescence stainings combined with RNA in situ hybridization by quantitative optical sectioning and image analysis. Transmission electron microscopy was used to study ultrastructural alterations. Renal functional, hemolysis, and complement system parameters were assessed in serum and urine.
Results
The mice developed a spontaneous phenotype with diffuse and global signs of glomerular TMA resulting in impaired kidney function, decreased body weight, and lifespan. The glomeruli were enlarged and showed thrombi, double contours of the glomerular basement membrane (GBM) with cell interposition, and endothelial cell swelling. Mesenchymal markers were expressed in a unique circular pattern around the capillaries in the glomerulus colocalized with the double contour of the GBM. The glomerular endothelial cells lost part of their characteristic endothelial markers, displayed de novo expression of mesenchymal markers, and showed ultrastructural features of mesenchymal cells, suggesting an endothelial-to-mesenchymal transition. The progressive course of the disease was further documented by the development of interstitial fibrosis and inflammatory cell infiltrations in the kidney cortex. No signs of hemolysis or serological evidence of complement activation were detected, suggesting a glomerular-limited disease.
Conclusion
The present mouse model showed typical signs of endothelial injury and glomerular remodeling found in TMA, revealing a novel pathological process of chronic glomerular injury in TMA via glomerular endothelial-to-mesenchymal transition.
Funding
- Government Support – Non-U.S.