Kidney Week

Abstract: FR-PO345

Pkd2 Re-Expression Can Reverse Liver Cysts and Improve GFR in Mouse Models of Autosomal Dominant Polycystic Kidney Disease

Session Information

• Genetic Diseases: Models, Mechanisms, Treatments
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Dong, Ke, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Ke Dong,

• Tham, Mingshen, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Mingshen Tham,

• Cordido, Adrian, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Adrian Cordido,

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

Yiqiang Cai,

• Pei, Steven Lim Cho, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Steven Lim Cho Pei,

• Bhardwaj, Rishi, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Rishi Bhardwaj,

• Wei, Zemeng, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Zemeng Wei,

• Rehman, Michael, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Michael Rehman,

• Roy, Kasturi, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Kasturi Roy,

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

Xin Tian,

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

Stefan Somlo,

Background

We have previously shown that PKD gene re-expression reverses polycystic kidney disease in inducible, whole nephron Cre mediated mouse models of ADPKD. We now sought to investigate the potential for cyst reversal in the Pkd2^WS25 mouse model in which macrocyst formation occurs by stochastic, non-Cre recombinase dependent, second hit events that better resemble the genetic mechanism of human ADPKD and allows determination of the potential to reverse both polycystic kidney and liver phenotypes.

Methods

Pkd2^WS25/- and tamoxifen inducible Pkd2-BAC re-expression (Pkd2^FSF;Rosa26^FlpoER) models previously established in the lab were intercrossed to generate Pkd2^WS25/-;Pkd2^FSF;Rosa26^FlpoER mice (Pkd2^WS25/Flpo). Pkd2 re-expression was induced with 7 daily intraperitoneal tamoxifen injections beginning at 16 weeks. Serial kidney MRI were obtained at 16, 19 and 24 weeks and kidney and liver histology was examined at 24 weeks. In addition, we used our published Pkd2^Cre/Flpo model with doxycycline induced Pkd2 inactivation at 4-6 weeks and reactivation at 16 weeks to measure serial GFR at 16 and 19 weeks.

Results

Compared to 16-week-old Pkd2^WS25/- mice, kidney weight/body weight ratio (1.812% vs 1.333%, P=0.0049), liver weight/body weight ratio (5.299% vs 4.371%, P=0.0198) and kidney cystic index (22.18% vs 7.164%, P=0.0002) were significantly reduced in 24-week-old Pkd2^WS25/Flpo mice following Pkd2 reactivation at 16 weeks. Moreover, MRI images shows progressive decrease in kidney cystic burden from 16 to 24 weeks. Kidney and liver histology at 24 weeks showed reduced cystic changes but persistent residual fibrosis and focal inflammation compared to 16-week-old Pkd2^WS25/- mice which exhibited multifocal cysts. Separately, Pkd2^Cre/Flpo mice which showed reduced GFR at 16 weeks before Pkd2 re-expression, had normalization of GFR at 19 weeks age, 3 weeks after Pkd2 re-expression (0.77 ml/min/100g vs 1.45 ml/min/100g, P=0.0032).

Conclusion

Pkd2 re-expression can reverse both kidney and liver cysts in a spontaneous, non-Cre recombinase dependent Pkd2 model that more closely recapitulates the human ADPKD phenotype with a smaller number of larger macrocysts. Furthermore, our follow-up study to our published data shows that improved GFR accompanies improved histology following Pkd gene re-expression.

Funding

• NIDDK Support