Kidney Week

Abstract: FR-PO551

Ouabain Enhances Renal Cyst Growth in a Slowly Progressive Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Session Information

• Genetic Diseases: Cystic - Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Trant, Jordan, University of Kansas Medical Center Department of Cell Biology and Physiology, Kansas City, Kansas, United States

Jordan Trant,

• De Blanco, Gladis Sanchez, University of Kansas Medical Center Department of Cell Biology and Physiology, Kansas City, Kansas, United States

Gladis Sanchez De Blanco,

• Mcdermott, Jeff P., University of Kansas Medical Center Department of Cell Biology and Physiology, Kansas City, Kansas, United States

Jeff P. Mcdermott,

• Blanco, Gustavo, University of Kansas Medical Center Department of Cell Biology and Physiology, Kansas City, Kansas, United States

Gustavo Blanco,

Background

Renal cyst progression in autosomal dominant polycystic kidney disease (ADPKD) is highly dependent on agents circulating in blood. We have previously shown, using different in vitro models, that one of these agents is the hormone ouabain. By binding to Na,K-ATPase (NKA), ouabain triggers a cascade of signal transduction events which enhance ADPKD cyst progression by stimulating cell proliferation, fluid secretion, and dedifferentiation of the renal tubular epithelial cells, all effects not seen in normal human kidney cells. The potential mechanism behind these effects is the abnormally high affinity that ~25% of the NKA of ADPKD cells have for ouabain. Here, we validate ouabain’s effects in vivo and show that NKA ouabain affinity is critical for these effects.

Methods

Low dose ouabain (0.01 or 0.03 mg/g) or saline was injected intraperitoneally to mice daily, starting at postnatal day 9 and continuing for 1-5 months. The mouse models used include wildtype (WT), a slowly progressive ADPKD model (Pkd1^RC/RC), and an ADPKD mouse model in which all NKA has a high ouabain affinity (Pkd1^RC/RCNKAα1^OS/OS). Kidney weight to body weight ratio (%KW/BW), blood urea nitrogen (BUN), renal percent cystic area (% cyst area), cyst number, and percent fibrosis were measured.

Results

Ouabain augmented % cyst area, cyst number, and renal fibrosis in Pkd1^RC/RC mice when compared to saline-administered controls. By contrast, ouabain had no significant effect on WT mice. Pkd1^RC/RCNKAα1^OS/OS mice receiving saline had significantly increased % cyst area, cyst number, %KW/BW, and % fibrosis than Pkd1^RC/RC mice receiving saline. Ouabain administration to Pkd1^RC/RCNKAα1^OS/OS mice did not alter any of the cystic parameters studied when compared to the saline-administered controls, and when compared to Pkd1^RC/RC mice receiving ouabain, only % cyst area and renal fibrosis were increased over the study period.

Conclusion

These findings demonstrate that ouabain at levels similar to those circulating in plasma stimulates kidney cyst progression in ADPKD in vivo as well as in vitro. Additionally, the ouabain affinity of NKA plays a key role in the hormone’s cystogenic effects.

Funding

• NIDDK Support