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Abstract: PO1717

Shiga Toxin Targets the Podocyte in Haemolytic Uraemic Syndrome (HUS) Resulting in Glomerular Endothelial Cell Complement Dysregulation

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Bowen, Emily Elizabeth, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Hurcombe, Jenny, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Keir, Lindsay S., University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Barrington, Fern, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Farmer, Louise K., University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Lay, Abigail Charlotte, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Welsh, Gavin Iain, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Larkai, Eva, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Saleem, Moin, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
  • Coward, Richard, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom

Group or Team Name

  • Bristol Renal
Background

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) that has a predilection to present in the kidney. It is a triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In 90% of cases, HUS follows gastroenteritis secondary to infection with Shiga toxin (Stx) producing bacteria such as Escherichia coli. Stx HUS is the leading cause of acute kidney injury in children with a mortality of 5%. However, the precise pathophysiological mechanisms following Stx infection leading to TMA remain poorly understood. Here we show that the podocyte is a key initiator in Shiga toxin HUS, which could explain why the glomerulus is the prime target of systemic Shiga toxin driven infection.

Methods

To demonstrate that the podocyte Shiga toxin receptor (Gb3) is sufficient to trigger the development of HUS, we used conditional gene targeting to engineer human Gb3 expression specifically in the podocytes of adult mice.

Results

Following intraperitoneal Shiga toxin challenge, these mice developed thrombocytopenia, haemolytic anaemia and uraemia (Figure 1) with evidence of glomerular TMA on histology. Interrogation of this model revealed evidence of glomerular endothelial cell complement activation, with loss of local complement factor H protection. Furthermore, C5 inhibition was found to rescue the Shiga toxin HUS phenotype.

Conclusion

Together, these observations provide compelling evidence for the importance of podocyte-glomerular endothelial cell cross-talk within the kidney in the development of Shiga toxin associated HUS and suggest a possible therapeutic role for complement inhibition in patients with this devastating disease.

Funding

  • Other NIH Support