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Abstract: FR-PO947

Loss of Robo2 in Mature Podocytes Is Protective from Injury by Enhancing Podocyte Adhesion That Helps Maintain Foot Process Structure

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Pisarek-Horowitz, Anna, Boston University Medical Center, Boston, Massachusetts, United States
  • Fan, Xueping, Boston University School of Medicine, Boston, Massachusetts, United States
  • Kumar, Sudhir, Boston University, Boston, Massachusetts, United States
  • Milo Rasouly, Hila, Columbia University, New York, New York, United States
  • Sharma, Richa, Boston University Medical Center, Boston, Massachusetts, United States
  • Chen, Hui, BMC, Boston, Massachusetts, United States
  • Beck, Laurence H., Boston University Medical Center, Boston, Massachusetts, United States
  • Henderson, Joel M., Boston University Medical Center, Boston, Massachusetts, United States
  • Salant, David J., Boston University Medical Center, Boston, Massachusetts, United States
  • Lu, Weining, Boston University Medical Center, Boston, Massachusetts, United States
Background

Repulsive guidance cue receptor ROBO2 plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known.

Methods

In this study, we compared phenotypes between adult Robo2 podocyte specific knockout mice (Robo2 cKO) and wildtype controls under two different glomerular injury conditions induced by protamine sulfate (PS) perfusion or nephrotoxic serum (NTS) injection. We also analyzed ROBO2 expressions in the glomeruli of NTS injured mice, passive Heymann nephritis (PHN) rat, and membranous nephropathy patients.

Results

Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better preserved slit-diaphragm density compared to wild-type littermates injured by either protamine sulfate (PS) or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is upregulated after glomerular injury since its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion.

Conclusion

These findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and thus loss of Robo2 in podocytes could be protective from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.

Funding

  • NIDDK Support –