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Abstract: FR-PO770

Elovl7 Enhances Podocyte Ferroptosis in Glomerulopathy by Participating in Polyunsaturated Fatty Acid Elongation

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

  • Kang, Minchao, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
  • Bai, Linnan, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
  • Li, Qiu-yu, Zhejiang University School of Medicine Children's Hospital, Hangzhou, Zhejiang, China
  • Wang, Yi, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  • Wu, Junnan, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
Background

Podocytes are terminally differentiated visceral epithelial cells that form a crucial part of the glomerular filtration barrier. Podocytopathy is becoming increasingly prevalent worldwide. However, the mechanisms underlying podocyte injury remain unclear. Numerous studies have attributed podocyte loss in glomerular diseases to apoptosis, and research on podocyte-targeting therapies has emerged. This study aims to elucidate the specific mechanisms of injury and the ultimate mode of death of podocytes.

Methods

We performed single-nucleus RNA sequencing (snRNA-seq) on kidney tissues from various glomerular diseases, including adriamycin-induced nephropathy (AN), chronic kidney disease (CKD), minimal change disease (MCD), and obesity-related glomerulopathy (ORG). Cell death pathway scoring on podocytes identified the predominant form of podocyte death. Gene enrichment analyses along with pseudo-time analysis revealed multiple lipid metabolism pathways associated with podocyte injury. Targeted lipidomics on adriamycin-stimulated Mpc5 cells (Mouse Podocyte Clone-5) and metabolic pathway scoring pinpointed changes in phospholipid types and lipid metabolism pathways. Conditional knockout mice and intracellular knockdown experiments were conducted to validate the impact of key gene in the lipid metabolism pathway we screened.

Results

Cell death pathway scoring on podocytes demonstrated elevated ferroptosis scores in nephropathies with severe podocyte injury, such as AN and CKD. Additionally, Injured podocytes had higher levels of phospholipids with long-chain unsaturated fatty acid side chains, which are sensitive to ferroptosis, compared to the control group. Metabolic pathway scoring revealed dysregulation of Elovl7-involved fatty acid elongation in the podocytes of the AN group. Podocyte-specific Elovl7 knockout in mice and Elovl7 knockdown in Mpc5 cells abolished the elevated levels of phospholipids with long-chain polyunsaturated fatty acids and lipid peroxides.

Conclusion

In summary, we found substantial podocyte loss and annotated a subset of injured podocytes in snRNA-seq data from podocytopathies. This may be due to the increased synthesis of long-chain polyunsaturated fatty acids mediated by Elovl7, which eventually leads to the accumulation of intracellular lipid peroxidation and ferroptosis.

Funding

  • Government Support – Non-U.S.