Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse

Abstract

Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently no targeted therapy is available for this disease. INVS/NPHP2 is one of the 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.

Data availability

No large scale datasets generated. Data analyzed can be found in source data files for figures 1-7, figure 4 figure supplement 1 and figure 7 figure supplement 1.

Article and author information

Author details

  1. Yuanyuan Li

    Department of Genetics, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wenyan Xu

    Department of Genetics, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Svetlana Makova

    Department of Pediatrics, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Martina Brueckner

    Department of Pediatrics, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zhaoxia Sun

    Department of Genetics, Yale University, new haven, United States
    For correspondence
    zhaoxia.sun@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2307-7719

Funding

NIH (R01DK113135)

  • Zhaoxia Sun

NIH (R01HD093608)

  • Zhaoxia Sun

NIH (R35HL145249)

  • Martina Brueckner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gregory G Germino, National Institutes of Health, United States

Ethics

Animal experimentation: All mouse experiments were performed in Yale University School of Medicine in accordance with Yale University Institutional Animal Care and Use Committee guidelines. Protocols were approved by Yale University Institutional Animal care and Use Committee (Protocol number: 2022-11546).

Version history

  1. Preprint posted: February 10, 2022 (view preprint)
  2. Received: August 2, 2022
  3. Accepted: March 14, 2023
  4. Accepted Manuscript published: March 15, 2023 (version 1)
  5. Version of Record published: May 2, 2023 (version 2)

Copyright

© 2023, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yuanyuan Li
  2. Wenyan Xu
  3. Svetlana Makova
  4. Martina Brueckner
  5. Zhaoxia Sun
(2023)
Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse
eLife 12:e82395.
https://doi.org/10.7554/eLife.82395

Share this article

https://doi.org/10.7554/eLife.82395

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