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Abstract: PO1554

Pathobiology of Cyst Progression in Nbce1A and Pkd1 (RC/RC) Mouse Models

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Anaam, Deema A., Radiology, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Holmes, Heather L., Physiology & Biomedical Engineering, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Gregory, Adriana, Radiology, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Thao, Ka, Nephrology & Hypertension, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Stiller, Alison, Physiology & Biomedical Engineering, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Harris, Peter C., Nephrology & Hypertension, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Kline, Timothy L., Radiology, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
  • Romero, Michael F., Physiology & Biomedical Engineering, Mayo Clinic Minnesota, Rochester, MN, Rochester, Minnesota, United States
Background

The Pkd1(RC/RC) mouse is a hypomorphic model of autosomal polycystic kidney disease (ADPKD) characterized by renal cortical and medullary cysts which increase in size and number with age. The nature of these cysts and how this epithelium differs from normal collecting duct epithelia is currently unknown. Moreover, as the phenotype is variable, the disease progression of any individual mouse is unknown. We also generated an isoform specific Na+ bicarbonate cotransporter knockout (Nbce1A-KO) mouse using TALENs. As with the whole gene knockout, these mice are severely acidotic but also present with cortical renal cysts. The nature of these cysts and their connection to NBCe1A protein expression is currently unknown.

Methods

We measure mouse (Bk6J) total kidney volume (TKV) using MRI (7T/16T) and ultrasound (US; SonoVol Vega). The Vega system allows 3D renal imaging and cardiac analysis (e.g., heart rate, ejection fraction, cardiac output). We follow renal function using transdermal GFR measurements. Lastly, kidneys are harvested, fixed, followed by immunofluorescence (IF) of cryosections with nephron segment specific markers or picrosirius red (collagen stain) of paraffin sections.

Results

A longitudinal study of Nbce1A-KO and RC/RC mice shows both models increased TKV (Fig A) measured by MRI or US (Fig B,C). Both show lower GFR [WT: 558±40, nbce1A-KO: 420±144, RC/RC: 276±63 µL/min/(100g-bw)]. Ejection fraction and stroke volume were preserved, while heart rate and cardiac output decreased in Nbce1A-KO and RC/RC mice (Fig A). Both Nbce1A-KO (Fig E) and RC/RC mice (Fig F) have collecting duct cysts, positive for AQP2 and cKit. Picrosirius red staining shows that these cystic structures have increased collagen thickening.

Conclusion

Taken together these data imply that cystogenesis in the RC/RC and nbce1A-KO models have similar pathobiology. Potentially this means that understanding how and why cysts develop in nbce1A-KOs may provide additional mechanistic information in ADPKD.

Funding

  • NIDDK Support