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Because a newly described salt-inducible kinase 1 (SIK1) network is responsible for increases in active cell sodium transport in response to elevated intracellular sodium, we hypothesized that this network could mediate the effects of the mutant (hypertensive) form of α-adducin on Na+,K+-ATPase activity.Studies were performed in normotensive and hypertensive Milan rats and in a cell line of proximal tubule origin expressing transiently variants of α-adducin (human G460W/S586C; rat F316Y) that are associated with elevated blood pressure and result in increased Na+,K+-ATPase activity. Na+,K+-ATPase activity was determined as ouabain-sensitive rubidium transport.SIK1 activity (T182 phosphorylation) was significantly elevated in renal proximal tubule cells from Milan hypertensive rats (carrying a α-adducin mutation) when compared with normotensive controls. Similarly, SIK1 activity (T182 phosphorylation) was elevated in a normal renal proximal tubule cell line when transfected with the α-adducin variant carrying the human hypertensive mutation. Blocking the SIK1 network using negative mutants as well as different stages of its activation pathway prevented the effects induced by the hypertensive α-adducin.The SIK1 network may constitute an alternative target by which agents can modulate active sodium transport in renal epithelia and avoid the increases in systemic blood pressure that are associated with genetic mutations in the human α-adducin molecule.