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

Nat Med. 2011 Oct 2;17(10):1304-9. doi: 10.1038/nm.2497.


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 use. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Bendroflumethiazide
  • Calcineurin Inhibitors*
  • Calcium / urine
  • Cell Line
  • Chlorides / urine
  • Creatinine / urine
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Humans
  • Hydrochlorothiazide
  • Hypertension / chemically induced*
  • Immunoblotting
  • Immunohistochemistry
  • Kidney / metabolism*
  • Mice
  • Mice, Knockout
  • Sodium Chloride Symporters / genetics
  • Sodium Chloride Symporters / metabolism*
  • Tacrolimus / adverse effects*
  • Tacrolimus / pharmacology


  • Calcineurin Inhibitors
  • Chlorides
  • Sodium Chloride Symporters
  • Hydrochlorothiazide
  • Bendroflumethiazide
  • Creatinine
  • Calcium
  • Tacrolimus