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Abstract: SA-OR22

Cell-Specific Role of STAT3 Signaling in Podocytes vs. Parietal Epithelial Cells in Proliferative Glomerulopathy

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Gowthaman, Yogesh, Stony Brook Medicine, Stony Brook, New York, United States
  • Guo, Yiqing, Stony Brook Medicine, Stony Brook, New York, United States
  • Pace, Jesse Alexander, Stony Brook Medicine, Stony Brook, New York, United States
  • Bronstein, Robert, Stony Brook Medicine, Stony Brook, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Salant, David J., Boston University School of Medicine, Boston, Massachusetts, United States
  • Mallipattu, Sandeep K., Stony Brook Medicine, Stony Brook, New York, United States
Background

Podocyte-specific loss of an essential zinc finger transcription factor Krüppel-like factor 4 (KLF4) triggers the activation of STAT3 in both podocytes and neighboring parietal epithelial cells (PECs), leading to podocyte loss, PEC activation and proliferation, and eventual FSGS. STAT3 is also activated in podocytes and PECs post-nephrotoxic serum (NTS) treatment, a model of proliferative glomerulopathy. Podocyte-specific loss of Stat3 preserves podocyte markers and attenuates PEC activation post-NTS treatment. However, the role of Stat3 in PECs has not previously been studied. The aim of this study is to investigate the cell-context-dependent role of STAT3 in inducing podocyte loss, but contributing to PEC activation and proliferation.

Methods

Podocin-Cre Klf4fl/fl;Stat3fl/fl (Klf4/Stat3-PODKO) mice were generated to test whether the loss of Stat3 prevents podocyte loss and subsequent PEC activation and FSGS in Klf4-PODKO mice, a model of proliferative glomerulopathy. Inducible and conditional loss of Stat3 was achieved in PECs by generating PEC-rtTA;TRE-Cre;Stat3fl/fl (Stat3-PECKO) after 2 weeks of doxycycline (DOX) treatment. Stat3-PECKO and wild-type mice were treated with nephrotoxic serum (NTS). STAT3-specific inhibitor, S3I-201, (control-DMSO) was administered in mice after NTS treatment to assess the effects of simultaneous pharmacological inhibition of STAT3 activation in podocytes and PECs.

Results

Klf4/Stat3-PODKO mice showed improved albuminuria, %FSGS lesion, preservation of podocyte markers (WT1 and synaptopodin) with a reduction in glomerular CD44 expression, indicating improvement in PEC activation as compared to Klf4-PODKO mice. Stat3-PECKO exhibited less PEC activation and proliferation, albuminuria, crescent formation, and FSGS compared to wild-type mice after NTS treatment. S3I-201 attenuated albuminuria, loss of podocyte markers (WT1, synaptopodin, podocin, and podocalyxin), PEC activation and proliferation (CD44), and FSGS lesions compared to DMSO post-NTS treatment.

Conclusion

STAT3 activation in podocytes induces podocyte loss, but in PECs contributes to PEC activation and proliferation in proliferative glomerulopathy.

Funding

  • NIDDK Support