Fatema Rafiqi for her PhD project, chose to study the role of the protein kinase SPAK that that had previously been discovered to be activated by the WNK1 kinase by an ex-MRC Unit PhD student, Alberto Vitari. Mutations that increase expression of WNK1 result in Gordon's Syndrome, a rare genetic disorder that is characterized by hypertension and hyperkalemia (high serum potassium). In order to address whether WNK regulated blood pressure via SPAK, Fatema generated a genetically modified mouse in which WNK1 can no longer switch SPAK on.

Excitingly, Fatema found with considerable help of Kevin O'Shaughnessy's lab in Cambridge as well as Aleksandar Jovanovict lab that the genetically modified SPAK mice have dramatically reduced blood pressure. In addition, there is reduced phosphorylation and expression of the kidney blood-pressure regulating ion cotransporters NCC and NKCC2, that Ciaran Richardson in the MRC Unit had previously shown to be phosphorylated and activated by SPAK. Consistent with these data, plasma and urine electrolyte measurements indicate that the mice display symptoms of salt wasting in particular when under a low-sodium diet.

This study is important as it provides strong genetic evidence that the WNK- SPAK-NCC/NKCC2 signalling network comprises a fundamental regulatory pathway involved in controlling blood pressure. Furthermore, our data suggest that drugs that inhibit SPAK kinase would be effective at lowering blood pressure by reducing the activity and expression of NCC and NKCC2. A recent

genome-wide association study revealed that intronic SNPs within the human SPAK gene (also known as STK39) could be linked to 20% of the population and lead to increased blood pressure. Together with our results the take home message is that SPAK is a master regulator of blood pressure in humans.

To read Fatema's paper click here.