How calcineurin inhibitors cause hypertension.

Calcineurin is a calcium-dependent serine–threonine protein phosphatase. Calcineurin activates the nuclear factor of activated T-cells cytoplasmic (NFAT)c, a transcription factor, by dephosphorylating the protein. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T-cell responses. Calcineurin is the target of a drug class called calcineurin inhibitors (CNI), which includes cyclosporine and tacrolimus. The NFAT transcription factor family consists of five members NFATc1, NFATc2, NFATc3, NFATc4 and NFAT5. Calcium signalling regulates NFATc1—NFATc4. In T cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. The tacrolimus macrolide prevents the dephosphorylation of NFAT by binding to the immunophilin, FK506 binding protein, thereby creating a new complex that reduces peptidylprolyl isomerase activity. This complex inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Pseudohypoaldosteronism type II (PHA-II) or familial hyperkalaemic hypertension (FHH) is a rare familial renal tubular defect characterized by hypertension and hyperkalaemic, non-anion gap metabolic acidosis in the presence of low renin and aldosterone levels. The molecular basis for most individuals who have PHA-II was linked to loss-of-function mutations in the ‘with-no-lysine’ kinases (WNK), either WNK1 or WNK4. The WNK kinases comprise a family of serine–threonine protein kinases with unusual placement of the catalytic lysine compared with all other protein kinases. WNK1 or WNK4 regulate chloride cotransporters of the distal nephron and other epithelia. The WNK kinase network and how it regulates sodium balance, potassium homeostasis and blood pressure has recently been reviewed [1, 2]. To fulfil their regulatory function, the WNK kinases interact with other important kinases, including serum and glucocorticoid-regulated kinase 1, STE20/SPS1related proline alanine-rich kinase (SPAK) and oxidative stress-responsive protein type 1 (OSR1) kinase. The resultant kinase network regulates the activity of the major sodium and potassium transporters in the distal nephron, including thiazide-sensitive Na–Cl cotransporters (NCC) and the renal outer medullary potassium channel (ROMK). WNK kinases modulate ion transport through two distinct regulatory pathways involving trafficking and phosphorylation. A schematic adapted from recent reviews is given in (Figure 1). Mice that lack a catalytically active SPAK are strikingly hypotensive with marked reduction in NCC phosphorylation in the kidney and exhibit reduced Na/ K/2Cl cotransporter (NKCC1) phosphorylation in the vessel wall [2]. SPAK and OSR1 kinases regulate SCL12A transporters with important physiological effects for sodium homeostasis by the kidney, aortic contractility and neuronal excitability. In vivo, SPAK plays a major role in the regulation of blood pressure and represents a potential target for diuretic development. Rare mutations in WNK kinases cause FHH. However, genetic variations in WNK kinases have been associated with salt-sensitive essential hypertension [1]. Furthermore, heterozygous inactivating mutations in this pathway may protect from hypertension. The pathway has also been implicated in the hypertension associated with Type 2 diabetes mellitus. Acquired syndromes exist that exhibited similar clinical characteristics as PHA-II. One such syndrome occurs in almost every patient undergoing renal transplantation. These patients are invariably treated with CNI. They generally develop hypertension that is commonly associated with non-anion gap (mild) metabolic acidosis and hyperkalaemia. Recently, Hoorn et al. [3] reported novel findings that may serve to explain the connection. The group hypothesized that CNI induce hypertension by stimulating NCC. They first studied wild-type mice and found that tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC, WNK3, WNK4 and SPAK compared to control mice. They then gave tacrolimus to mice with a gene-disrupted NCC. Tacrolimus could not increase blood pressure in these mice. However, the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. The blood pressure increases to tacrolimus were reversed by hydrochlorothiazide treatment. The investigators also included human studies. They showed that kidney transplant