ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-PO785

Murine Model of Glomerular Thrombotic Microangiopathy Results in Glomerular Endothelial-to-Mesenchymal Transition

Session Information

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.