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Kidney Week

Abstract: FR-PO578

Epithelial-Mesenchymal Cross-Talks in Murine Models of Renal Ciliopathy

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Sun, Zhaoxia, Yale University School of Medicine Department of Genetics, New Haven, Connecticut, United States
  • Hsieh, Chia-Ling, Yale University School of Medicine Department of Genetics, New Haven, Connecticut, United States
  • Li, Yuanyuan, Yale University School of Medicine Department of Genetics, New Haven, Connecticut, United States
  • Xu, Wenyan, Yale University School of Medicine Department of Genetics, New Haven, Connecticut, United States
  • Makova, Svetlana Z., Yale University School of Medicine Department of Pediatrics, New Haven, Connecticut, United States
  • Brueckner, Martina, Yale University School of Medicine Department of Pediatrics, New Haven, Connecticut, United States
Background

Ciliary defects underpin a variety of renal ciliopathies, including polycystic kidney disease and Nephronophthisis (NPHP). Both epithelial and stromal abnormalities are manifested in these diseases. Previously, to clarify the role of different cell types in disease progression, we utilized tissue specific mouse models of Arl13b, a cilia biogenesis gene, and Invs/Nphp2, a NPHP gene that encodes a protein localized to the proximal part of the cilium. Our results showed that epithelial specific knockout of Arl13b or Invs/Nphp2 was sufficient to cause both epithelial cyst and interstitial fibrosis. By contrast, stromal specific knockout of Invs/Nphp2 showed no obvious renal phenotypes up to the young adult stage, suggesting that epithelial cells are the main driver of the phenotypes and abnormal signaling from epithelial cells triggers interstitial fibrosis. Moreover, when Arl13b was specifically deleted in epithelial cells, Hedgehog signaling (HH) was activated non-cell autonomously in stromal cells and global pharmacological inhibition of HH signaling ameliorated fibrosis, kidney function decline and cyst progression, revealing a critical role of epithelial-mesenchymal crosstalk in disease progression. Combined, these results highlighted not only the importance of epithelial cells, but also epithelial-mesenchymal communications that include HH signaling in the molecular etiology of renal ciliopathy. However, the role of cilia in stromal response to epithelial signaling remains unclear.

Methods

In this study, we generated genetic mutants with Invs/Nphp2 and cilia biogenesis genes deleted in both epithelial and stromal cells and will investigate the renal phenotypes of the mutant mice. We further investigated cilia distribution in stromal cells.

Results

Our results suggest that cilia are present on stromal cells. Further phenotypic analysis will reveal whether cilia and Invs/Nphp2 in stromal cells modify the phenotypes triggered by defective epithelial cells.

Conclusion

Tissue specific function of cilia and ciliary genes plays a role in epithelial-mesenchymal crosstalks in renal ciliopathy.

Funding

  • NIDDK Support