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

Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE

Publication: New York Ny : Nature Publishing Company
Original Publication: New York, NY : Nature Pub. Co., [1995-

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

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.

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K01 DK076617 United States DK NIDDK NIH HHS; R01 DK051496 United States DK NIDDK NIH HHS; T32 DK067864 United States DK NIDDK NIH HHS; R01 DK51496 United States DK NIDDK NIH HHS

0 (Calcineurin Inhibitors)
0 (Chlorides)
0 (Sodium Chloride Symporters)
0J48LPH2TH (Hydrochlorothiazide)
5Q52X6ICJI (Bendroflumethiazide)
AYI8EX34EU (Creatinine)
SY7Q814VUP (Calcium)
WM0HAQ4WNM (Tacrolimus)

Date Created: 20111004 Date Completed: 20111207 Latest Revision: 20250529

20250530

PMC3192268

10.1038/nm.2497

21963515