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Abstract: FR-OR52

APOL1 Promotes Endothelial Cell Activation Beyond the Glomerulus

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Carracedo, Miguel, AstraZeneca PLC, Gothenburg, Sweden
  • Ericson, Elke, AstraZeneca PLC, Gothenburg, Sweden
  • Ågren, Rasmus, AstraZeneca PLC, Gothenburg, Sweden
  • Forslöw, Anna, AstraZeneca PLC, Gothenburg, Sweden
  • Madeyski-Bengtson, Katja, AstraZeneca PLC, Gothenburg, Sweden
  • Riddle, Rebecca B., University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
  • Christoffersson, Jonas, AstraZeneca PLC, Gothenburg, Sweden
  • González-King Garibotti, Hernán, AstraZeneca PLC, Gothenburg, Sweden
  • Lazovic, Bojana, AstraZeneca PLC, Gothenburg, Sweden
  • Greasley, Peter J., AstraZeneca PLC, Gothenburg, Sweden
  • Lal, Mark, AstraZeneca PLC, Gothenburg, Sweden
Background

Apolipoprotein-L1 (APOL1) high-risk genotypes are associated with increased risk of chronic kidney disease (CKD) in people of African ancestry. APOL1 is endogenously expressed in the kidney by podocytes, and endothelial cells (ECs). Interestingly, despite the abundant APOL1 expression in the endothelium little attention has been given to this cell type. Given the importance of ECs in the development and progression of CKD we hypothesized that APOL1 high-risk genotypes may promote EC activation and dysfunction.

Methods

To test out hypothesis we performed bioinformatic analysis of publicly available transcriptomics datasets from human and transgenic mice. In vitro, we expressed APOL1 in ECs derived from genetically modified induced pluripotent stem cells (iPSCs) as well as in transfected primary glomerular ECs.

Results

In this study, we show the high expression of endogenous APOL1 and its inducibility in various vascular beds of the kidney. Utilizing two datasets of glomeruli from patients with nephrotic syndrome and focal segmental glomerulosclerosis, we identified an increase in intercellular adhesion molecule-1 (ICAM-1) expression and an enrichment in leukocyte migration pathways in patients carrying APOL1 high-risk genotypes. This signature of EC activation was confirmed by analyzing publicly available RNA-seq data from podocyte-specific APOL1 transgenic mice, which presented a 4,9 and 2,8-fold increase in VCAM-1 and ICAM-1, respectively. In both ECs derived from genetically modified iPSCs and primary human glomerular ECs we show that APOL1 expression induced EC activation in a non-phlogistic manner. Specifically, APOL1 overexpression promoted changes in adhesion molecules, endothelial junctional proteins, inflammatory receptors, and intracellular complexity leading to an increase in monocyte attachment.

Conclusion

Overall, our data support the involvement of APOL1 as an inducer of EC activation and dysfunction, both in vivo and in vitro, in multiple vascular beds with effects beyond the glomerular vasculature.

Funding

  • Commercial Support