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Abstract: FR-PO910

Synaptopodin Deficiency Exacerbates Renal Disease in a Mouse Model of Alport Syndrome

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Ning, Liang, Washington University, Saint Louis, Missouri, United States
  • Suleiman, Hani, Washington University, Saint Louis, Missouri, United States
  • Miner, Jeffrey H., Washington University School of Medicine, St. Louis, Missouri, United States
Background

Synaptopodin (Synpo) is a proline-rich actin-associated protein found in podocyte foot processes and dendritic spines. It has been reported (Asanuma et al., J Clin Invest 2005) that Synpo-/- mice lack Synpo-short and Synpo-long isoforms but show an upregulation of Synpo-T (truncated) in podocytes. Synpo-/- mice show an overtly abnormal phenotype in the brain but not in the kidney, demonstrating that Synpo-T may serve as a backup for Synpo-long in Synpo-/- podocytes.
X-linked Alport syndrome is caused by mutations in COL4A5, which encodes the collagen IV α5 chain, resulting in structural and functional abnormalities of the glomerular basement membrane and leading to ESRD. It has been reported that expression of synaptopodin was decreased in Alport syndrome patients. We predicted that the deletion of Synpo in mice would exacerbate the effects of a Col4a5 mutation.

Methods

To directly investigate the role that Synpo plays in Alport syndrome, we crossed mutant mice carrying null mutations in Synpo and Col4a5 to produce mice deficient in one, both, or neither of these genes. Urine and tissues were taken at select time points to evaluate albuminuria, histopathology, and glomerular capillary wall ultrastructure.

Results

We generated novel Synpo-/- mice that should completely lack all known Synpo isoforms, but we did not observe obvious abnormalities in the kidneys. We found that the ablation of Synpo in Col4a5-/- or Col4a5-/Y mice led to shortened life span and acceleration of disease progression, such as more severe proteinuria and glomerulosclerosis. We obtained the same results except for decreased life span in Col4a5+/- females; surprisingly, most Col4a5+/- mice could live 5 months regardless of the presence or absence of Synpo. Immunostaining showed that the expression of COL4A345 was upregulated in these mosaic female mice in the absence of Synpo.

Conclusion

We conclude that Synpo deletion exacerbates the Alport syndrome disease phenotype in Alport mice, revealing the podocyte actin cytoskeleton as a target for therapy.

Funding

  • NIDDK Support