Key result
Blocking the SIK1 network prevented the increases in active cell sodium transport induced by the hypertensive alpha-adducin mutation in renal proximal tubule cells.
Why the study?
Does blocking the SIK1 network prevent increases in cell sodium transport caused by hypertension-linked mutations in alpha-adducin in renal proximal tubule cells?
Does blocking the SIK1 network prevent increases in cell sodium transport caused by hypertension-linked mutations in alpha-adducin in renal proximal tubule cells?
Blocking the SIK1 network prevents increased active cell sodium transport caused by hypertension-linked alpha-adducin mutations, identifying a potential novel target for hypertension treatment.
Hypothesis-generating for SIK1 as hypertension target; leaves open translation from animal cells to in vivo or human disease.
OBJECTIVES: 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 alpha-adducin on Na,K-ATPase activity. METHODS: Studies were performed in normotensive and hypertensive Milan rats and in a cell line of proximal tubule origin expressing transiently variants of alpha-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. RESULTS: SIK1 activity (T182 phosphorylation) was significantly elevated in renal proximal tubule cells from Milan hypertensive rats (carrying a alpha-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 alpha-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 alpha-adducin. CONCLUSION: 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 alpha-adducin molecule.
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Stenström et al. (2009) studied Hypertension. Blocking the SIK1 network vs. Unblocked / normotensive controls was evaluated on SIK1 activity (T182 phosphorylation) and Na,K-ATPase activity. Blocking the SIK1 network prevented the increases in active cell sodium transport induced by the hypertensive alpha-adducin mutation in renal proximal tubule cells.
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