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:

The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension

Nature Medicine volume 17, pages 1304–1309 (2011)Cite this article

Subjects

This article has been updated

Abstract

Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria and acidosis, often complicate their use1,2. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.

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: Effects of tacrolimus on arterial pressure and electrolyte handling in mice.
Figure 2: Effects of tacrolimus on transport proteins and kinases in kidney and in vitro.
Figure 3: Effects of tacrolimus on systolic blood pressure (SBP), sodium handling and NCC abundance in mice in which NCC was deleted, inhibited or overexpressed.
Figure 4: Functional data and immunostaining in human subjects with CNI-induced hypertension compared with controls.

Similar content being viewed by others

Change history

  • 13 January 2012

     In the version of this article initially published, the dose and route of administration of tacrolimus were inadvertently omitted. Tacrolimus or vehicle was administered subcutaneously; the dose of tacrolimus was 1 mg per kg body weight per day. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Kim, H.C. et al. Primary immunosuppression with tacrolimus in kidney transplantation: three-year follow-up in a single center. Transplant. Proc. 36, 2082–2083 (2004).

    Article  CAS  Google Scholar 

  2. Jain, A. et al. What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann. Surg. 230, 441–448, discussion 448–449 (1999).

    Article  CAS  Google Scholar 

  3. Nijenhuis, T., Hoenderop, J.G. & Bindels, R.J. Downregulation of Ca2+ and Mg2+ transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. J. Am. Soc. Nephrol. 15, 549–557 (2004).

    Article  CAS  Google Scholar 

  4. Mohebbi, N., Mihailova, M. & Wagner, C.A. The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins. Am. J. Physiol. Renal Physiol. 297, F499–F509 (2009).

    Article  CAS  Google Scholar 

  5. Takeda, Y., Miyamori, I., Furukawa, K., Inaba, S. & Mabuchi, H. Mechanisms of FK 506-induced hypertension in the rat. Hypertension 33, 130–136 (1999).

    Article  CAS  Google Scholar 

  6. Curtis, J.J., Luke, R.G., Jones, P. & Diethelm, A.G. Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. Am. J. Med. 85, 134–138 (1988).

    Article  CAS  Google Scholar 

  7. Kang, C.B., Hong, Y., Dhe-Paganon, S. & Yoon, H.S. FKBP family proteins: immunophilins with versatile biological functions. Neurosignals 16, 318–325 (2008).

    Article  CAS  Google Scholar 

  8. Smith, K.D. et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J. Am. Soc. Nephrol. 14, 1037–1045 (2003).

    Article  CAS  Google Scholar 

  9. Gooch, J.L., Roberts, B.R., Cobbs, S.L. & Tumlin, J.A. Loss of the alpha-isoform of calcineurin is sufficient to induce nephrotoxicity and altered expression of transforming growth factor-beta. Transplantation 83, 439–447 (2007).

    Article  CAS  Google Scholar 

  10. McCormick, J.A., Nelson, J.H., Yang, C.L., Curry, J.N. & Ellison, D.H. Overexpression of the sodium chloride cotransporter is not sufficient to cause familial hyperkalemic Hypertension. Hypertension published online, doi:10.1161HYPERTENSIONAHA.110.167809 (6 September 2011).

  11. Esteva-Font, C. et al. Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2). Nephrol. Dial. Transplant. 22, 2810–2816 (2007).

    Article  CAS  Google Scholar 

  12. Anselmo, A.N. et al. WNK1 and OSR1 regulate the Na+, K+, 2Cl− cotransporter in HeLa cells. Proc. Natl. Acad. Sci. USA 103, 10883–10888 (2006).

    Article  CAS  Google Scholar 

  13. Yang, C.L., Angell, J., Mitchell, R. & Ellison, D.H. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J. Clin. Invest. 111, 1039–1045 (2003).

    Article  CAS  Google Scholar 

  14. San-Cristobal, P. et al. Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc. Natl. Acad. Sci. USA 106, 4384–4389 (2009).

    Article  CAS  Google Scholar 

  15. Melnikov, S., Mayan, H., Uchida, S., Holtzman, E.J. & Farfel, Z. Cyclosporine metabolic side effects: association with the WNK4 system. Eur. J. Clin. Invest. 41, 1113–1120 (2011).

    Article  CAS  Google Scholar 

  16. Schultheis, P.J. et al. Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl− cotransporter of the distal convoluted tubule. J. Biol. Chem. 273, 29150–29155 (1998).

    Article  CAS  Google Scholar 

  17. Hu, D.C., Burtner, C., Hong, A., Lobo, P.I. & Okusa, M.D. Correction of renal hypertension after kidney transplantation from a donor with Gitelman syndrome. Am. J. Med. Sci. 331, 105–109 (2006).

    Article  Google Scholar 

  18. Colussi, G. et al. A thiazide test for the diagnosis of renal tubular hypokalemic disorders. Clin. J. Am. Soc. Nephrol. 2, 454–460 (2007).

    Article  CAS  Google Scholar 

  19. Madala Halagappa, V.K., Tiwari, S., Riazi, S., Hu, X. & Ecelbarger, C.M. Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat. Am. J. Physiol. 294, F1222–F1231 (2008).

    Google Scholar 

  20. Feng, M. et al. Genetic analysis of blood pressure in 8 mouse intercross populations. Hypertension 54, 802–809 (2009).

    Article  CAS  Google Scholar 

  21. Koomans, H.A. & Ligtenberg, G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation 72, S9–S12 (2001).

    Article  CAS  Google Scholar 

  22. Curtis, J.J. Hypertensinogenic mechanism of the calcineurin inhibitors. Curr. Hypertens. Rep. 4, 377–380 (2002).

    Article  Google Scholar 

  23. Segal, A.S., Hayslett, J.P. & Desir, G.V. On the natriuretic effect of verapamil: inhibition of ENaC and transepithelial sodium transport. Am. J. Physiol. Renal Physiol. 283, F765–F770 (2002).

    Article  Google Scholar 

  24. Paver, W.K. & Pauline, G.J. Hypertension and hyperpotassemia without renal disease in a young male. Med. J. Aust. 2, 305–306 (1964).

    CAS  Google Scholar 

  25. Calò, L., Davis, P.A. & Semplicini, A. Control of vascular tone in the syndromes of Bartter and Gitelman. Crit. Rev. Clin. Lab. Sci. 37, 503–522 (2000).

    Article  Google Scholar 

  26. Calò, L., Davis, P.A. & Semplicini, A. Reduced content of alpha subunit of Gq protein content in monocytes of Bartter and Gitelman syndromes: relationship with vascular hyporeactivity. Kidney Int. 61, 353–354 (2002).

    Article  Google Scholar 

  27. Guyton, A.C. Blood pressure control—special role of the kidneys and body fluids. Science 252, 1813–1816 (1991).

    Article  CAS  Google Scholar 

  28. Adu, D., Michael, J., Turney, J. & McMaster, P. Hyperkalemia in cyclosporine treated renal allograft recipients. Lancet 322, 370–372 (1983).

    Article  Google Scholar 

  29. Heering, P.J. et al. Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression. Clin. Transplant. 18, 186–192 (2004).

    Article  CAS  Google Scholar 

  30. Higgins, R. et al. Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities. Nephrol. Dial. Transplant. 19, 444–450 (2004).

    Article  CAS  Google Scholar 

  31. Van Laecke, S. et al. Posttransplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation. Am. J. Transplant 9, 2140–2149 (2009).

    Article  CAS  Google Scholar 

  32. Arthur, J.M. & Shamim, S. Interaction of cyclosporine and FK506 with diuretics in transplant patients. Kidney Int. 58, 325–330 (2000).

    Article  CAS  Google Scholar 

  33. Schindler, R., Tanriver, Y. & Frei, U. Hypertension and allograft nephropathy—cause, consequence, or both? Nephrol. Dial. Transplant. 15, 8–10 (2000).

    Article  CAS  Google Scholar 

  34. Feng, M. et al. Validation of volume-pressure recording tail-cuff blood pressure measurements. Am. J. Hypertens. 21, 1288–1291 (2008).

    Article  Google Scholar 

  35. Kurtz, T.W., Griffin, K.A., Bidani, A.K., Davisson, R.L. & Hall, J.E. Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood pressure measurement in experimental animals: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension 45, 299–310 (2005).

    Article  CAS  Google Scholar 

  36. Yang, C.-L., Zhu, X. & Ellison, D.H. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J. Clin. Invest. 117, 3403–3411 (2007).

    Article  CAS  Google Scholar 

  37. Welker, P. et al. Renal Na+-K+-Cl− cotransporter activity and vasopressin-induced trafficking are lipid raft-dependent. Am. J. Physiol. 295, F789–F802 (2008).

    CAS  Google Scholar 

  38. Piechotta, K., Lu, J. & Delpire, E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J. Biol. Chem. 277, 50812–50819 (2002).

    Article  CAS  Google Scholar 

  39. Yang, S.S. et al. Mechanisms for hypercalciuria in pseudohypoaldosteronism type II–causing WNK4 knock-in mice. Endocrinology 151, 1829–1836 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

For technical assistance, we thank N. Desmerais (animal studies), S. Rogers, K. Risowsky (immunohistochemistry), D. Gannon and A. Bakke (tacrolimus measurements in mice). We thank G. Jones and M. Harber for help in identifying human subjects. We also thank G. Shull (University of Cincinnati) for the NCC-knockout mice, and E. Delpire (Vanderbilt Kennedy Center) for SPAK antibodies. E.J.H. is supported by an Erasmus Medical Center Fellowship and Kolff Junior Postdoc Grant (Dutch Kidney Foundation, KJPB 08.004); J.A.M. is supported by the US National Institutes of Health (NIH) (K01 DK076617); D.H.E. is supported by the NIH (RO1 DK51496), the Department of Veterans Affairs (Merit Review) and the American Heart Association (10 GRNT 2630199). Portions of this work were presented at the High Blood Pressure Research Council Meeting of the American Heart Association, 13–16 October 2010, and the American Society of Nephrology, 15–18 November 2010.

Author information

Author notes

  1. Ewout J Hoorn, Stephen B Walsh, Robert J Unwin and David H Ellison: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Nephrology & Hypertension, Oregon Health & Science University, Portland, Oregon, USA

    Ewout J Hoorn, James A McCormick, Chao-Ling Yang, James Conley & David H Ellison

  2. UCL Centre for Nephrology, University College London, London, UK

    Stephen B Walsh, Antje Fürstenberg & Robert J Unwin

  3. Department of Anatomy, Charité, Berlin, Germany

    Tom Roeschel, Alexander Paliege & Sebastian Bachmann

  4. Department of Pathology, University College London, London, UK

    Alexander J Howie

  5. Veterans Affairs Medical Center, Portland, Oregon, USA

    David H Ellison

Authors
  1. Ewout J Hoorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen B Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James A McCormick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antje Fürstenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao-Ling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tom Roeschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexander Paliege
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexander J Howie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James Conley
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sebastian Bachmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Robert J Unwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David H Ellison
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.J.H. and S.B.W. carried out most of the experiments, analyzed the data and wrote the initial manuscript. J.A.M. generated the mice overexpressing the NCC and participated in animal experiments and analyses. J.C. did the aldosterone infusion experiments. A.F. contributed to the human experiments and, together with A.J.H., to the kidney biopsy tissue staining. C.-L.Y. conducted the cell studies. T.R., A.P. and S.B. carried out the calcineurin immunohistochemistry. R.J.U. and D.H.E. conceived of the study, supervised the work and edited the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to David H Ellison.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–6 and Supplementary Figures 1–4 (PDF 379 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoorn, E., Walsh, S., McCormick, J. et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med 17, 1304–1309 (2011). https://doi.org/10.1038/nm.2497

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2497

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