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Kidney Week

Abstract: FR-PO715

Therapeutic Targeting Strategies in Pkd1 Loss-of Function Mouse Model: Insights into Pkd1 Regulation

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Kurbegovic, Almira, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada
  • Parrot, Camila, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada
  • Trudel, Marie, Institut de recherches cliniques de Montreal, Montreal, Quebec, Canada

Autosomal dominant polycystic kidney disease (ADPKD) causes renal and extrarenal phenotypes, mainly due to PKD1 mutations. As a therapeutic strategy, CRISPR-Cas is attractive but the high frequency of off-targets precludes clinical application. Because microscopic cysts are likely formed in utero in ADPKD kidneys, we targeted at early renal stage wild type Pkd1/Pc1 protein from 3 series of transgenic (Tg) lines in Pkd1-/- mouse, to assess for long-term cure/improvement of severe renal and pancreatic cysts and neonatal death.


Re-expression of Pc1 was generated via three Tg matings: a) a systemic Pkd1TAG mouse (16 Tg copy) b) 2 renal-specific SBPkd1TAG mice (2 and 20 Tg copy) or c) a novel Tg line targeting Pkd1 cDNA with renal-specific elements, SBP (16 Tg copy). Longitudinal molecular and histologic analyses were performed on kidneys and pancreas.


Pkd1TAG;Pkd1-/- mice expressing 7-fold over the endogenous Pkd1 gene are totally rescued from renal or pancreatic phenotypes. From 8 mo onwards, Pkd1TAG;Pkd1-/- mice, relative to parental Tg line, display later renal cysts consistent with gene-dosage increase pathogenic mechanism. SBPkd1TAG;Pkd1-/- mice with mild ~0.64 or notable 7-fold renal Pc1 overexpression are rescued from neonatal death. In the mild expressor with Tg copies comparable to endogenous, renal and pancreatic cysts are detected at P5 and deaths occurs at P10-P15 whereas the high expressor display renal cysts later at P15 but no pancreatic cysts and survive up to ~3 mo. Renal cysts develop likely from differential tubular and temporal regulatory response to Pc1 either insufficient or over-expression. SBP;Pkd1-/- mice with 0.87-fold Pkd1 endogenous level exhibit very mild renal cyst formation at P0 and escape neonatal lethality. This targeting strategy required multiple SBP Tg copies to produce Pkd1 therapeutic levels similar to the SBPkd1TAG and provided evidence for regulatory region within the Pkd1 gene-body. Identification of cystic nephron segments will shed light on the mechanism.


Our results demonstrate that Tg foetal Pc1 expression can substantially delay cystogenesis and extend mouse lifespan. This study shows that Pc1 re-expression not only requires high spatiotemporal regulation by the Pkd1 upstream region but also by regulatory elements within the Pkd1 gene-body.


  • Government Support - Non-U.S.