Kidney Week

Abstract: TH-PO596

Compound-Homozygous Pkd1 and Pkd2 Inactivation Has No Additive Effect on Cyst Formation

Session Information

• Cystic Kidney Diseases - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Tian, Xin, Yale University School of Medicine, New Haven, Connecticut, United States

Xin Tian,

• Cai, Yiqiang, Yale University School of Medicine, New Haven, Connecticut, United States

Yiqiang Cai,

• Ma, Ming, Yale University School of Medicine, New Haven, Connecticut, United States

Ming Ma,

• Zhang, Chao, Yale University School of Medicine, New Haven, Connecticut, United States

Chao Zhang,

• Besse, Whitney E., Yale University School of Medicine, New Haven, Connecticut, United States

Whitney E. Besse,

• Gulati, Ashima, Yale University School of Medicine, New Haven, Connecticut, United States

Ashima Gulati,

• Somlo, Stefan, Yale University School of Medicine, New Haven, Connecticut, United States

Stefan Somlo,

Background

Autosomal dominant polycystic kidney disease results from mutations in PKD1 or PKD2. The two genes work together in a common signaling pathway in which PKD1 is the rate limiting step. We previously showed an extra-additive increase in cystogenic events in Pkd1+/-;Pkd2+/- mice that may result from a modified threshold effect. In the current study, we examined whether there is a similar effect with conditional homozygous inactivation of both genes in mouse kidney collecting ducts.

Methods

We generated Pkd1fl/fl;Pkd2fl/fl;Pkhd1Cre mice which inactivate both genes in collecting ducts by postnatal day 7 (P7). Pkd1fl/fl;Pkd2fl/fl;Pkhd1Cre mice (n=7), Pkd1fl/fl;Pkhd1Cre mice (n=8) and Pkd2fl/fl;Pkhd1Cre mice (n=7) were examined at P14, P24 and P48.

Results

Histological and functional examination of kidneys from Pkd1fl/fl;Pkd2fl/fl;Pkhd1Cre mice at P14 and P24 showed no significant difference in kidney-body weight ratio (KW/BW), cystic index (CI) and BUN when compared with Pkd1fl/fl;Pkhd1Cre mice. When compared with Pkd2fl/fl;Pkhd1Cre mice, both groups had statistically significant increase in KW/BW (P<0.05), CI (P<0.05) and BUN (P<0.05) at both time points. At P48, multiple comparison showed no significant differences in any parameter among the three groups. We also documented normal appearance of cilia by immunofluorescence microscopy in the cyst lining cells of Pkd1fl/fl;Pkd2fl/fl;Pkhd1Cre mice. There was no significant difference in cyst cell proliferation by BrdU incorporation and apoptotic activity by TUNEL between Pkd1fl/fl;Pkd2fl/fl;Pkhd1Cre mice and Pkd1fl/fl;Pkhd1Cre mice at P14, P24 and P48. However, both these groups had significantly higher cell proliferation rates when compare to Pkd2fl/fl;Pkhd1Cre mice at P14 (P<0.05). Notably, all three groups has significantly increased apoptosis at P48 when compared to P24 and P14.

Conclusion

Dual inactivation of Pkd1 and Pkd2 shows no additive effect on cyst formation but early stage inactivation of Pkd1 results in more rapid cyst growth than inactivation of Pkd2, likely due to longer persistence of the Pkd2 protein. Late stage models show genotype-independent increase in apoptosis.

Funding

• NIDDK Support