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

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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.

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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.

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.

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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.

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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.

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Correspondence to David H Ellison.

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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

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