ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO1008

Repurposing Tolvaptan, a Drug for Polycystic Kidney Disease, for Renal Cell Carcinoma Therapy

Session Information

  • Onco-Nephrology: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Onco-Nephrology

  • 1500 Onco-Nephrology

Authors

  • Dwivedi, Nidhi, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Sinha, Sonali, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Jamadar, Abeda, University of Kansas Medical Center, Kansas City, Kansas, United States
  • Calvet, James P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Rao, Reena, University of Kansas Medical Center, Kansas City, Kansas, United States
Background

The vasopressin type-2 receptor (V2R) plays an essential role in the regulation of salt and water homeostasis by the kidneys. Based on a serendipitous finding that V2R is ectopically expressed in human clear cell renal cell carcinoma (ccRCC) tumors, the current studies examined if V2R plays a pathogenic role in ccRCC tumor growth. The effect of Tolvaptan, an FDA approved drug for hyponatremia and polycystic kidney disease was also tested.

Methods

V2R expression was examined using the cancer genome atlas database, and analysis of human RCC tumor tissue microarrays, cDNA arrays and tumor biopsy samples. In vitro and in vivo mouse tumor xenograft studies were performed to determine V2R’s role in ccRCC tumor growth and test therapeutic interventions.

Results

V2R expression and activity, suggested by high intracellular cAMP and phosphorylated ERK1/2 (pERK1/2), levels were detected in human ccRCC tumors. The V2R antagonists OPC31260 and Tolvaptan, as well as V2R gene silencing reduced in vitro clonogenicity, wound closure and cell viability of 786-O and Caki-1 human ccRCC cell lines. V2R antagonists reduced pERK1/2 levels, while V2R agonist increased cAMP and pERK1/2 levels. Tolvaptan and OPC31260 also decreased RCC tumor growth in mouse xenograft models by reducing cell proliferation and angiogenesis, while increasing apoptosis. In contrast, the V2R agonist dDAVP significantly increased tumor growth.

Conclusion

These results provide novel evidence for the pathogenic role of V2R signaling in ccRCC and suggest that V2R antagonists, including the FDA approved drug Tolvaptan, could be utilized as novel therapeutics for ccRCC.

Funding

  • NIDDK Support