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Cardiovasc Ther. 2011 Feb;29(1):68-76. doi: 10.1111/j.1755-5922.2010.00180.x. Epub 2010 Dec 19.

Hypertension, dietary salt intake, and the role of the thiazide-sensitive sodium chloride transporter NCCT.

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1
Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Cambridge, UK.

Abstract

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.

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