A high
salt intake in industrialized countries is an important cardiovascular risk factor. It remains at typically twice the maximum recommended levels of 5-6 g/day, and halving this would have enormous public health benefit in preventing
stroke and
cardiovascular disease.
Salt homeostasis can also be affected pharmacologically by
diuretic drugs that target mechanisms within the distal kidney nephron to cause
salt wasting. Indeed,
thiazide-type
diuretics are among the most widely used agents in the management of
hypertension and work by blocking NCCT, the NaCl-transporter in the distal nephron. The biology of this
membrane transporter was not previously well understood until the discovery of the molecular basis of a rare familial form of
hypertension called
Gordon syndrome (
pseudohypoaldosteronism type 2, PHAII). This has established that the NCCT transporter is dynamically regulated in the kidney by WNK
kinases and a signaling cascade using a second
kinase called SPAK. Common polymorphisms in the SPAK gene have recently been shown to affect blood pressure in human cohorts and removing its function lowers blood pressure in mice. The SPAK-deficient mouse actually has a phenotype reminiscent of
Gitelman syndrome. This suggests that specific inhibitors of SPAK
kinase may provide a novel class of
diuretic drugs to lower blood pressure through
salt wasting. The expectation is that SPAK inhibitors would mimic the on-target effects of
thiazides but not their adverse off-target effects. An
antihypertensive drug that could lower blood pressure with the efficacy of a
thiazide without producing metabolic side effects such as hyperuricaemia or
impaired glucose tolerance is therapeutically very attractive. It also exemplifies how data coming from the rare monogenic
hypertension syndromes can together with genome-wide association studies in
hypertension deliver novel druggable targets.