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

Calcineurin inhibitors (CNIs) are immunosuppressive drugs, which are used widely to prevent rejection of transplanted organs and treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria, and acidosis often complicate their use(1,2). These side effects resemble familial hyperkalemic hypertension (FHHt), a genetic disease characterized by overactivity of the renal sodium chloride co-transporter (NCC), and caused by mutations in 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. The functional importance of NCC in this response was demonstrated by showing that tacrolimus did not affect blood pressure in NCC knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice over-expressing NCC. Moreover, hydrochlorothiazide reversed tacrolimus-induced hypertension. In kidney transplant recipients treated with tacrolimus, fractional chloride excretion in response to bendroflumethiazide was greater than in controls, and renal NCC abundance was also greater, extending these observations to humans. Together, these findings indicate that tacrolimus-induced 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.