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Kidney Week

Abstract: FR-PO748

Notch Overexpression in a Mouse Model of Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Belyea, Brian C., University of Virginia, Charlottesville, Virginia, United States
  • Sequeira Lopez, Maria Luisa S., University of Virginia, Charlottesville, Virginia, United States
  • Gomez, Roberto Ariel, University of Virginia, Charlottesville, Virginia, United States
Background

Polycystic kidney disease (PKD) is a major cause of end stage renal disease and characterized by enlarged kidneys containing numerous fluid-filled cysts, hypertension, anemia, and progressive loss of kidney function. PKD is autosomal dominant (ADPKD), caused by mutations in the PKD1 or PKD2 genes, or autosomal recessive (ARPKD), caused by mutations in the PKHD1 gene. While the genetic basis of PKD is known, the downstream molecular mechanisms which lead to deregulation of proliferation, apoptosis, and differentiation remain poorly understood. Previous work has demonstrated Notch activation in mouse models of ADPKD and ARPKD. In addition, we have shown that aberrant Notch signaling during kidney development leads to an alterations in cell fate. Thus, we hypothesize that Notch overexpression during kidney development may play an important role in PKD pathogenesis.

Methods

We generated transgenic mice with overexpression of Notch1 in renin lineage cells using the Cre-lox system. Specifically, we crossed mice which express Cre recombinase under the control of the renin locus (Ren1dcre/+) with transgenic mice containing a sequence encoding an intracellular portion of the mouse Notch1 gene inserted into the ubiquitously expressed Rosa26 locus (RosaNotch/+). Control mice (Ren1d+/+;RosaNotch/Notch) and mutant mice (Ren1dcre/+;RosaNotch/+) were studied at 3, 6, and 9 months of age.

Results

Mutant mice developed large kidneys with numerous cysts by 3 months of age and this phenotype worsened with advancing age. Histologic examination confirmed the presence of numerous cysts throughout the kidney cortex of mutant mice. Mutant animals had decreased Renin expression shown by PCR and decreased RENIN protein levels in the kidney and plasma as shown by immunohistochemistry and ELISA respectively. In addition, mutant animals developed anemia and worsening renal function with age. Finally, mutant animals did not live beyond 9 months of life, likely dying secondary to renal failure and/or anemia.

Conclusion

Mice with overexpression of Notch1 in renin lineage cells develop numerous renal cysts, enlarged kidneys, anemia, progressive renal insufficiency and early death – recapitulating many features of human PKD. To our knowledge, this is the first model of PKD resulting from overexpression of Notch signaling, and this work highlights the importance of aberrant Notch signaling in PKD.

Funding

  • NIDDK Support