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Abstract: PO1724

Effect of Glomerular Disease on the Podocyte Cell Cycle

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Perin, Laura, Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Nicolas Frank, Camille H., Harvard Medical School, Boston, Massachusetts, United States
  • Hou, Xiaogang, Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Clair, Geremy, Pacific Northwest National Laboratory Biological Sciences Division, Richland, Washington, United States
  • Salem, Fadi E., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • De Filippo, Roger E., Children's Hospital of Los Angeles, Los Angeles, California, United States
  • Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lemley, Kevin V., Children's Hospital of Los Angeles, Los Angeles, California, United States
Background

Progression of glomerulosclerosis is associated with loss of podocytes and subsequent glomerular tuft instability. A decreased number of podocytes may be able to preserve tuft stability through cell hypertrophy associated with cell cycle re-entry. At the same time, re-entry into the cell cycle can lead to podocyte detachment from the glomerular basement membrane, if podocytes cross the G1/S checkpoint and undergo abortive cytokinesis.

Methods

To study cell cycle dynamics during CKD development, we used a FUCCI mouse model (fluorescence ubiquitination-based cell cycle indicator) affected by X-linked Alport Syndrome (AS). This model has progressive CKD and expresses cell cycle fluorescent reporters exclusively in podocytes. We quantified podocytes cell cycle distribution in WT and AS mice at different ages and collected podocytes in G0 and G1 for proteomics studies.

Results

We showed that with the development of CKD, an increasing fraction of podocytes in vivo are in G1 or later cell cycle stages. G1 and G2 podocytes are hypertrophic. Heterozygous female mice, with milder manifestations of CKD, show G1 fraction numbers intermediate between WT and male AS mice. Proteomic analysis showed differences in cytoskeleton re-organization and metabolic processes between podocytes in G0 and G1 in disease vs. WT and indicate alteration of specific proteins also identified in human AS podocytes.

Conclusion

Our data showed that, during progressive CKD, the podocyte cell cycle distribution changes dramatically, suggesting that cell cycle manipulation may have a role in the treatment of various progressive glomerular diseases characterized by podocytopenia.

Funding

  • Private Foundation Support