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Kidney Week

Abstract: FR-PO569

Pkd2 Deficiency in Embryonic Aqp2+ Progenitor Cells Is Sufficient to Cause Severe Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Tsilosani, Akaki, Albany Medical Center, Albany, New York, United States
  • Gao, Chao, Albany Medical Center, Albany, New York, United States
  • Shehzad, Sana A., Albany Medical Center, Albany, New York, United States
  • Chen, Enuo, Albany Medical Center, Albany, New York, United States
  • Sharma, Madhulika, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Tran, Pamela Vivian, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Bates, Carlton M., UPMC Children's Hospital of Pittsburgh Child Development Unit, Pittsburgh, Pennsylvania, United States
  • Wallace, Darren P., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Zhang, Wenzheng, Albany Medical Center, Albany, New York, United States
Background

Most cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by mutations in PKD1 or PKD2, which encode polycystin-1 and polycystin-2, respectively. The mechanism for renal cyst formation remains unclear. We showed that embryonic Aqp2+ progenitor cells (AP) give rise to principal cells (PC) and intercalated cells (IC) to generate the distal renal segments consisting of the late distal convoluted tubules (DCT2), connecting tubules (CNTs), and collecting ducts (CDs). Adult AP also contribute to the renal tissue maintenance and injury repair by regenerating DCT2/CNT/CD cells. Here, we tested the hypothesis that ablation of Pkd2 in embryonic AP is sufficient to induce PKD.

Methods

Aqp2Cre Pkd2f/f mice were generated to disrupt Pkd2 in embryonic AP. Aqp2ECE/+ Pkd2f/f mice were tamoxifen-inducted at P1 or P60 to disrupt Pkd2 in neonate or adult AP and PC, respectively, and sacrificed 7 months after Cre induction. Immunofluorescence was done to assess cell types that lined the cysts. Cells were categorized and quantified. We also analyzed cyst-lining cells in four other PKD mouse models (cpk, Six2creFrs2αKO, Pkd1RC/RC and Thm1CKO), and compared staining between ADPKD patients and normal controls.

Results

Pkd2 is expressed in all segments from proximal tubule to CD, and in all CNT/CD cell types. Pkd2f/f Aqp2Cre mice developed severe PKD and died ~P17. The kidneys showed a reduced IC to PC ratio and a complete lost of α-IC by P12. Cysts extended from the CD to DCT1 and possibly to the loop of Henle, but not to the proximal tubules. Pkd2f/f Aqp2Cre mice had obvious cysts by P6 with rare α-IC . IC were more apoptotic than PC. Ablation of Pkd2 in neonate or adult AP and PC in Aqp2ECE/+ Pkd2f/f mice did not cause PKD. Cyst-lining α-IC were found in the other PKD models. AQP2+ cells were found in the cysts of only 13 out of 27 ADPKD samples, which had a diminished IC to PC ratio. None of the ADPKD kidneys had α-IC within the AQP2+ cysts.

Conclusion

Pkd2 deletion in embryonic AP, but not in neonate or adult Aqp2+ cells (PC and AP), was sufficient for PKD development. IC, particularly α-IC, were selectively depleted in Pkd2f/f Aqp2Cre mice and ADPKD patients. We proposed that Pkd2 is critical for maintenance of cystic α-IC.

Funding

  • NIDDK Support