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Kidney Week

Abstract: FR-PO948

c-Myc Is a Modulator of Pkd1 Gene and Polycystic Kidney Disease Progression

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Parrot, Camila, Institut de Recherches Cliniques de Montreal, Montreal, Quebec, Canada
  • Kurbegovic, Almira, Institut de Recherches Cliniques de Montreal, Montreal, Quebec, Canada
  • Yao, Guanhan, Institut de Recherches Cliniques de Montreal, Montreal, Quebec, Canada
  • Trudel, Marie, Institut de Recherches Cliniques de Montreal, Montreal, Quebec, Canada
Background

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common disorders associated mainly with Pkd1/Pc1 mutations. Orthologous Pc1 dosage-reduced and -increased mouse models develop renal tubular cysts. A causal connection between c-Myc-targeted overexpression and PKD was determined from transgenic SBM mice that closely resemble ADPKD and orthologous mouse models. Using these mouse models, we investigated for a clear regulatory interplay and signaling crosstalk between c-Myc and Pkd1 or Pc1.

Methods

Kidney tissues of SBM and four Pc1-dosage models were analyzed for molecular expression at mRNA levels by qPCR, at protein levels by WB and for cellular expression by IHC. Pkd1 gene regulation was assessed in vivo using genome ChIP analysis. Direct causal connection was interrogated by in vivo genetic interactions.

Results

We showed that renal regulation in four Pc1 dosage-reduced and -increased mouse models converge toward stimulation of c-Myc expression along with β-catenin (~5-10-fold) in tubular epithelial cells as in ADPKD renal tissues. This systematic increase defined c-Myc as a key Pkd1 node in cystogenesis and confered the high relevance of the SBM transgenic mice for further analysis. Enhanced c-Myc in SBM transgenic mice led conversely to striking upregulation of Pkd1/Pc1 expression (~10-fold) and β-catenin activation, uncovering reciprocal crosstalk between c-Myc and Pc1. In adult SBM kidneys, c-Myc ChIP analysis showed strongly enriched binding on Pkd1 promoter associated with RNA pol II, consistent with Pkd1 upregulation during cystogenesis. Similar c-Myc direct binding also at birth uncovered an equivalent role on Pkd1 regulation during renal developmental program, suggesting a role in condensing metanephric mesenchymal stem cells as for c-Myc. These data revealed an inter-regulatory network of c-Myc and Pc1 in normal physiologic and PKD conditions and shed light on PKD1 upregulation in the face of human ADPKD mutation. Genetic ablation of c-Myc in Pc1-reduced and -increased mouse models significantly attenuates cyst growth, proliferation and PKD progression, providing evidence that c-Myc is a Pkd1 causal cystogenic factor.

Conclusion

Together our data determined a dual role for c-Myc, as a major contributor in a feed-forward regulatory Pkd1–c-Myc loop mechanism and in Pc1-induced cystogenesis that may also prevail in human ADPKD.

Funding

  • Government Support - Non-U.S.