Pathogenesis of calcineurin inhibitor-induced hypertension

Abstract

This article reviews the current understanding of the mechanisms of calcineurin inhibitor-induced hypertension. Already early after the introduction of cyclosporine in the 1980s, vasoconstriction, sympathetic excitation and sodium retention by the kidney had been shown to play a role in this form of hypertension. The vasoconstrictive effects of calcineurin inhibitors are related to interference with the balance of vasoactive substances, including endothelin and nitric oxide. Until recently, the renal site of the sodium-retaining effect of calcineurin inhibitors was unknown. We and others have shown that calcineurin inhibitors increase the activity of the thiazide-sensitive sodium chloride cotransporter through an effect on the kinases WNK and SPAK. Here, we review the pertinent literature on the hypertensinogenic effects of calcineurin inhibitors, including neural, vascular and renal effects, and we propose an integrated model of calcineurin inhibitor-induced hypertension.

Conflict of interest statement

Conflict of interest statement: None.

Figures

Fig. 1

Model for the effects of calcineurin inhibitors on vascular tone, sympathetic nervous system and kidney sodium retention. Question marks refer to interactions that have been shown in other studies, but not in the context of CNIs (10, 11). Ang II = angiotensin II; NCC = sodium chloride cotransporter; ROS = reactive oxygen species; SNS = sympathetic nervous system; SPAK = Ste20-related kinase; WNK = with no K (K = lysine).

Fig. 2

Mean arterial pressures (MAP) (average of 5 measurements each day for each patient) of the cyclosporine- and azathioprine-treated groups. Patients had similar MAP values on the control diet (150 mEq). With sodium restriction, the cyclosporine group had a significant (p

Fig. 3

Hypothetical model for the effect of tacrolimus on the sodiumchloride cotransporter (NCC). An epithelial cell in the distal convoluted tubule (DCT) is shown. Tacrolimus (also FK506) binds to its intracellular binding protein (FKBP). This complex inhibits calcineurin (CaN). Because calcineurin is a phosphatase, it may inhibit some kinases under basal conditions. In the DCT, the kinases WNK3, WNK4 and SPAK interact to phosphorylate and activate NCC. Therefore, tacrolimus may prevent inhibition of these kinases by calcineurin, allowing phosphorylation and activation of NCC. This model is largely based on experiments reported in (56).