Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist

Nature Medicine volume 9, pages 1323–1326 (2003)Cite this article

Abstract

The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts1,2. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3′,5′-cyclic monophosphate (cAMP) has a major role in cystogenesis3,4, and the VPV2R is the major cAMP agonist in the collecting duct5,6. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Polycystin pathway can influence intracellular regulation of Ca2+ and cAMP in collecting-duct epithelial cells from polycystic kidneys.
Figure 2: Renal levels of cAMP, VPV2R and aquaporin-2 mRNA.
Figure 3: Effects of OPC32160 treatment at the specified concentrations on the development (3–10 weeks for PCK rats; 4–30 weeks for pcy mice) and progression (10–18 weeks for PCK rats; 15–30 weeks for pcy mice) of PKD in animal models.
Figure 4: Representative kidney sections from PCK rats and CD1/pcy mice treated with OPC32160 and from untreated controls.

Similar content being viewed by others

References

  1. Zerres, K. & Mucher, G. Autosomal recessive polycystic kidney disease. J. Mol. Med. 76, 303–309 (1998).

    Article  CAS  Google Scholar 

  2. Hildebrandt, F. & Otto, E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J. Am. Soc. Nephrol. 11, 1753–1761 (2000).

    CAS  PubMed  Google Scholar 

  3. Yamaguchi, T. et al. cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int. 57, 1460–1471 (2000).

    Article  CAS  Google Scholar 

  4. Hanaoka, K. & Guggino, W. cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J. Am. Soc. Nephrol. 11, 1179–1187 (2000).

    CAS  PubMed  Google Scholar 

  5. Yasuda, G. & Jeffries, W.B. Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int. 54, 80–86 (1998).

    Article  CAS  Google Scholar 

  6. Wallace, D.P., Rome, L.A., Sullivan, L.P. & Grantham, J.J. cAMP-dependent fluid secretion in rat inner medullary collecting ducts. Am. J. Physiol. Renal Physiol. 280, F1019–F1029 (2001).

    Article  CAS  Google Scholar 

  7. Koulen, P. et al. Polycystin-2 is an intracellular calcium release channel. Nat. Cell Biol. 4, 191–197 (2002).

    Article  CAS  Google Scholar 

  8. Nauli, S.M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    Article  CAS  Google Scholar 

  9. Qian, Q. et al. Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum. Mol. Genet. 12, 1875–1880 (2003).

    Article  CAS  Google Scholar 

  10. Chabardes, D., Imbert-Teboul, M. & Elalouf, J.M. Functional properties of Ca2+-inhibitable type 5 and type 6 adenylyl cyclases and role of Ca2+ increase in the inhibition of intracellular cAMP content. Cell Signal. 11, 651–663 (1999).

    Article  CAS  Google Scholar 

  11. Yamaguchi, T., Nagao, S., Kasahara, M., Takahashi, H. & Grantham, J. Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am. J. Kidney Dis. 30, 703–709 (1997).

    Article  CAS  Google Scholar 

  12. Gattone, V.H., Maser, R.L., Tian, C., Rosenberg, J.M. & Branden, M.G. Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Develop. Gen. 24, 309–318 (1999).

    Article  CAS  Google Scholar 

  13. Parnell, S.C. et al. The polycystic kidney disease-1 protein, polycystin-1, binds and activates heterotrimeric G-proteins in vitro. Biochem. Biophys. Res. Commun. 251, 625–631 (1998).

    Article  CAS  Google Scholar 

  14. Ward, C.J. et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat. Genet. 30, 259–269 (2002).

    Article  Google Scholar 

  15. Olbrich, H. et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat. Genet. 34, 455–459 (2003).

    Article  CAS  Google Scholar 

  16. Promeneur, D., Kwon, T.-H., Frokler, J., Knepper, M.A. & Nielsen, S. Vasopressin V2-receptor-dependent regulation of AQP2 expression in Brattleboro rats. Am. J. Physiol. Renal Physiol. 279, F370–F382 (2000).

    Article  CAS  Google Scholar 

  17. Ward, C.J. et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum. Mol. Genet.; published online 12 August 2003 (doi:10.1093/hmg/ddg274).

  18. Cass, L.A. et al. Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation. Mol. Cell Biol. 19, 5882–5891 (1999).

    Article  CAS  Google Scholar 

  19. Yamaguchi, T., Wallace, D.P., Grantham, J.J. & Calvet, J.P. Decreased intracellular Ca2+, which causes an ADPKD-like switch in the proliferative response of M-1 cells to cAMP, is associated with increased activation of Src, B-Raf, and ERK, and increased B-Raf protein. J. Am. Soc. Nephrol. 13, 105A (2002).

    Google Scholar 

  20. Yamamura, Y. et al. Characterization of a novel aquaretic agent, OPC–31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br. J. Pharmacol. 105, 787–791 (1992).

    Article  CAS  Google Scholar 

  21. Wong, L.L. & Verbalis, J.G. Vasopressin V2 receptor antagonists. Cardiovasc. Res. 51, 391–402 (2001).

    Article  CAS  Google Scholar 

  22. Thibonnier, M., Coles, P., Thibonnier, A. & Shoham, M. The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu. Rev. Pharmacol. Toxicol. 41, 175–202 (2001).

    Article  CAS  Google Scholar 

  23. Ohnishi, A. et al. Aquaretic effect of a potent, orally active, nonpeptide V2 antagonist in men. J. Pharmacol. Exp. Ther. 272, 546–551 (1995).

    CAS  PubMed  Google Scholar 

  24. Gabow, P. et al. The clinical utility of renal concentrating capacity in polycystic kidney disease. Kidney Int. 35, 675–680 (1989).

    Article  CAS  Google Scholar 

  25. Verani, R.R. & Silva, F.G. Histogenesis of the renal cysts in adult (autosomal dominant) polycystic kidney disease: a histochemical study. Mod. Pathol. 1, 457–463 (1988).

    CAS  PubMed  Google Scholar 

  26. Wu, G. et al. Somatic inactivation of PKD2 results in polycystic kidney disease. Cell 93, 177–188 (1998).

    Article  CAS  Google Scholar 

  27. Sutters, M. et al. Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells. Kidney Int. 60, 484–494 (2001).

    Article  CAS  Google Scholar 

  28. Junqueira, L.C.U., Bignolas, G. & Brentani, R.R. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem. J. 11, 447–455 (1979).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the PKD Foundation and the Indiana University School of Medicine (V.H.G.) and by National Institutes of Health grant DK44863 (V.E.T.). OPC31260 was a gift from Otsuka Pharmaceutical. C. Trambaugh, A. Yu and M. Branden provided technical assistance.

Author information

Authors and Affiliations

  1. Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, 46202, Indiana, USA

    Vincent H Gattone II

  2. Division of Nephrology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Xiaofang Wang, Peter C Harris & Vicente E Torres

Authors
  1. Vincent H Gattone II
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaofang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter C Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vicente E Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vincent H Gattone II or Vicente E Torres.

Ethics declarations

Competing interests

V.H.G. is listed as the inventor on the US patent, held by the University of Kansas Medical Center, entitled, “Treatment of polycystic kidney disease using vasopressin V2 receptor antagonists.”

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gattone, V., Wang, X., Harris, P. et al. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 9, 1323–1326 (2003). https://doi.org/10.1038/nm935

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm935

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing