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Abstract: PO1515

Heterozygous Loss of Pkd2 Accelerates Cystogenesis in Pkd1RC/RC Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Daniel, Emily A., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Metcalf, July P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Dai, Yuqiao, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Zhang, Yan, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 (~85% of cases) or PKD2 (~10% of cases), which encode polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively. The sporadic nature of cyst formation led to the hypothesis that cystogenesis requires a two-hit mechanism, involving a germline mutation (first hit) and somatic mutation (second hit) in the PKD gene. More recent evidence indicates that reducing normal PC-1 expression below a critical threshold is sufficient to initiate cyst formation. To further investigate the role of gene dosing, we evaluated the effect of knocking out one allele of Pkd2 on the onset and progression of cystogenesis in the Pkd1RC/RC (R3277C) hypomorphic mouse model that develops mild cystic disease over several months (Hopp, et al. J CIin Invest., 2012).

Methods

Pkd2+/- mice (Wu et al. Cell, 1998), which have normal kidneys, were crossed with Pkd1RC/RC mice to generate Pkd1RC/RC; Pkd2+/- mice. Body weight (BW), two kidney weight (KW), KW/BW, and cystic index were compared between Pkd1RC/RC; Pkd2+/- and Pkd1RC/RC littermates from 1 week to 9 months. Cystic index and blood urea nitrogen (BUN) were also measured.

Results

There was no difference in BW between the Pkd1RC/RC; Pkd2+/- and Pkd1RC/RC mice. We found that Pkd1RC/RC; Pkd2+/- mice developed early cystogenesis with rapid increases in KW and cystic index up to 8 weeks of age. The KW/BW of Pkd1RC/RC; Pkd2+/- mice was twice that of Pkd1RC/RC mice at 8 weeks (3.0 ± 0.2 vs. 1.5 ± 0.1%) and cystic index was also significantly higher (32.0 ± 3.8 vs. 5.6 ± 3.7%). At 9 months, KW/BW of the Pkd1RC/RC; Pkd2+/- mice remained elevated compared to Pkd1RC/RC mice (3.2 ± 0.2 vs. 1.7 ± 0.1%). Cystic index was 21.0 ± 0.7 and 6.4 ± 2.1% for the Pkd1RC/RC; Pkd2+/- and Pkd1RC/RC kidneys, respectively. Pkd1RC/RC; Pkd2+/- mice also had elevated renal fibrosis and BUN levels at 9 months, consistent with a decline in renal function.

Conclusion

This study demonstrates that heterozygous loss of Pkd2 accelerated the onset of cystogenesis in Pkd1RC/RC mice, supporting the hypothesis that PC-1 and PC-2 function in a common pathway and that lowering the expression of the polycystins is sufficient to initiate cystogenesis. We think that the increased progression of cystic disease in Pkd1RC/RC; Pkd2+/- mouse makes it a promising model for evaluating therapeutic interventions.

Funding

  • NIDDK Support