ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

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

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0626

Extracellular Vesicles Rescue Alport Glomerular Endothelial Lipid Dysfunction

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Soloyan, Hasmik, Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Thornton, Matthew Edward, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Angeletti, Andrea, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Perin, Laura, Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Sedrakyan, Sargis, Children's Hospital of Los Angeles, Los Angeles, California, United States
Background

Glomerular endothelial dysfunction plays a key role in the development of chronic kidney disease (CKD). We have previously shown that glomerular endothelial cells (GEC) are damaged in Alport syndrome mice (AS, characterized by mutations in collagen IVα3α4α5), manifested by enlarged fenestrations and damaged glycocalix in the early stage of the disease. In the present study we report on the role of altered fatty acid utilization pathways leading to GEC dysfunction in AS, and the role of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) in re-establish lipid homeostasis.

Methods

GEC were isolated from tdTomato-reporter AS and WT mice at 4 months of age by FACS and transcriptome was analyzed and compared by bulk RNA-seq. Tissue samples from patients with AS were used to confirm our findings by immunohistochemistry. In vitro, silencing experiments using human primary GEC were performed to study the role of decreased fatty acid synthase (FASN) in GEC dysfunction, and AFSC-EVs (which contain FASN in their cargo) were applied as a rescue strategy to normalize FASN level and restore lipid homeostasis. Data were confirmed using AFSC-EV FASN-/-.

Results

AS GEC were highly enriched for differentially expressed genes associated with cellular metabolism, and lipid metabolism in particular. Genes associated with fatty acid transport (CD36, FATP-1, FATP-2, Fabp3) and synthesis (FASN) among others were downregulated, which was further associated with glomerular accumulation of lipid droplets in mice. We observed similar findings in human biopsy samples from AS patients by histology. In vitro, AFSC-EVs were able to rescue FASN deficiency and improve GEC function, unlike AFSC-EV FASN-/-.

Conclusion

We report for the first time a lipid metabolic dysfunction in Alport GEC, and the ability of AFSC-EVs to rescue this phenotype. Therefore, better understanding of the functional role of GEC in AS could lead to the development of targeted new therapies for the treatment of this and other forms of CKD.

Funding

  • Private Foundation Support