Hypertension affects ∼25% of adults in industrialized societies, and significantly increases the risk of heart attacks, strokes and kidney failure. However, the molecular abnormalities that underlie the most common forms of hypertension are poorly understood. This situation is changing, though, as a result of research on several rare monogenic forms of high and low blood pressure. By studying one such disorder — pseudohypoaldosteronism type II (PHAII) — Wilson et al. have now provided evidence for a new pathway that governs blood pressure.

Previous work studying different families with PHAII had linked the disease to regions on chromosomes 1, 12 and 17, but no convincing candidate genes had been identified. The key breakthrough for Wilson et al. came from the identification of a new PHAII-affected family, in which it proved possible to link the disease to a deletion in the first intron of WNK1, which encodes a serine/threonine kinase. Confirmation of the role of WNK1 in PHAII came from another family with chromosome-12-related PHAII with a different, but overlapping, intronic deletion in WNK1, which leads to a fivefold increase in its expression.

Next, by searching the human genome for genes related to WNK1, the authors found one such gene — WNK4 — in the PHAII-linked region on chromosome 17. Screening families with PHAII linked to chromosome 17 revealed four families with missense mutations that cluster in a short, highly conserved segment of WNK4, which were suggested to result in a gain of function.

So, what might be the role of the identified WNK proteins? Hypertension in PHAII patients has been attributed to increased reabsorption of salt by the kidneys. Consistent with this, the mouse homologues Wnk1 and Wnk4 were both present in a region of the kidney that has a key role in maintaining the body's salt and water balance. Combining these observations with the fact that the features of PHAII are chloride dependent led the authors to propose that WNKs are part of a pathway that regulates chloride ion uptake by the kidney. Increased activity of WNKs could then result in greater chloride ion retention, which would be compensated for by retaining more sodium ions, leading to greater water retention, higher blood volume and consequently higher blood pressure.

But do variants in WNK1 and WNK4 contribute to hypertension in the general population? Intriguingly, the genomic region that contains WNK4 has also been linked to blood-pressure variation in a large population by the Framingham Heart Study, hinting at this possibility. Whether or not this is the case, drugs targeting the pathway in which WNKs are involved could prove to be good antihypertensive agents.