Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase.

The renal proximal tubule (RPT) is a central locale for Na+ reabsorption, and blood pressure regulation. Na+ reabsorption in the RPT depends upon the Na,K-ATPase, which is controlled by a complex regulatory network, including Salt-Inducible Protein Kinase (SIK). SIKs are recently discovered members of the AMP-activated Protein Kinase (AMPK) family, which regulate salt homeostasis and metabolism in a number of tissues. In the RPT, SIK interacts with the Na,K-ATPase in the basolateral membrane (BM), regulating both the activity and level of Na,K-ATPase in the BM. Thus, Na,K-ATPase activity can be rapidly adjusted in response to changes in Na+ balance. Long-term changes in Na+ intake affect the state of SIK phosphorylation, and as a consequence the phosphorylation of TORCs, Transducers of Regulated CREB (cAMP Regulatory Element Binding Protein). Once phosphorylated, TORCs enter the nucleus, and activate transcription of the ATP1B1 gene encoding for the Na,K-ATPase beta subunit.