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Abstract: TH-PO780

Cross-Talk of Injured Podocytes with Parietal Epithelial Cells Through Wnt4/β-Catenin Signaling

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Daniel, Christoph, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
  • Schwartze, Eike, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
  • Pfister, Eva, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
  • Endlich, Nicole, Universitat Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
  • Drenic, Vedran, Universitat Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
  • Shankland, Stuart J., University of Washington, Seattle, Washington, United States
  • Pippin, Jeffrey W., University of Washington, Seattle, Washington, United States
  • Buettner, Maike Julia, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
  • Amann, Kerstin U., Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
Background

With changing demographics, chronic kidney disease (CKD) and its treatment have become a major public health concern. However, glomerulopathies such as FSGS have limited treatment options. Therefore, understanding the pathogenesis of these lesions, including gender differences, is critical to expanding therapeutic options.

Methods

Here we investigated podocyte injury and crosstalk with parietal epithelial cells (PECs) using both male and female transgenic rats expressing the human diphtheria toxin receptor (hDTR) in podocytes under the control of the podocin promoter. Podocyte injury was induced by injection of diphtheria toxin and disease progression/repair was assessed on days 3, 7, 14, 21. 28 and 42 by immunohistochemistry and real-time PCR. An in vitro podocyte injury model and PECs were used to further investigate the mechanisms of cellular crosstalk.

Results

After injection of diphtheria toxin into transgenic animals, we observed a loss of WT1-positive podocytes starting on day 7. The percentage of glomeruli with FSGS lesions and the number of Pax8-positive PECs on the glomerular tuft increased with time and correlated significantly (r=0.927, p<0.001). Interestingly, proteinuria at day 14 was approximately twice as high in males, and FSGS lesions and Pax8-positive cells on the tuft tended to be higher in males compared to females. From d14, both glomerular mRNA and protein expression of Wnt4 were increased, which was more pronounced in male animals. Wnt4 was localized in podocytes and beta-catenin in Pax8-positive lesions as shown by confocal microscopy. The Wnt4 target gene CD44 was strongly upregulated at d7 after model induction and then slowly increased after an initial decrease until the end of the experiment (d42). In cell culture, we confirmed that injured podocytes expressed and secreted Wnt4. Cell culture supernatants stimulated the expression of Wnt target genes Axin2 and beta-catenin in PECs but not in podocytes.

Conclusion

Taken together, these data suggest that the canonical Wnt/b-catenin axis plays a critical role in the crosstalk between PECs and injured podocytes and the subsequent migration of PECs onto the tuft. Furthermore, gender-specific differences in podocyte injury and regeneration appear to be, at least in part, Wnt4-mediated.

Funding

  • Government Support – Non-U.S.