Type 1 salt-inducible kinases (SIK1) has been shown to act as a mediator during 
the cellular adaptation to variations in intracellular sodium in a variety of 
cell types. Type 2 SIK (SIK2) modulates various biological functions and acts as 
a signal transmitter in various pathways. To evaluate the role of both SIK 
isoforms in renal and intestinal Na+,K+-ATPase (NKA) activity, we made use of 
constitutive sik1-/- (SIK1-KO), sik2-/- (SIK2-KO), double sik1-/-sik2-/- (double 
SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) 
or chronic high-salt (HS, 8% NaCl) diet intake for 48 h or 12 weeks. Long-term 
HS intake in WT was accompanied by 2-fold increase in jejunal NKA activity and 
slight (~30% reduction) decreases in NKA in the ileum and cecum; none of these 
changes was accompanied by changes in the expression of α1-NKA. The ablation of 
SIK1 and SIK2 prevented the marked increase in jejunal NKA activity following 
the long-term HS intake. The ablation of SIK1 and SIK2 in mice on a long-term HS 
intake impacted differently in the ileum and cecum. The most interesting finding 
is that in SIK2-KO mice marked reductions in NKA activity were observed in the 
ileum and cecum when compared to WT mice, both on normal and long-term HS 
intake. In summary, SIK1 or SIK2 ablation on chronic high-salt intake is 
accompanied by modulation of NKA along the intestinal tract, which differ from 
those after an acute high-salt intake, and this may represent an absorptive 
compensatory mechanism to keep electrolyte homeostasis.