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Essential hypertension is a complex condition whose cause involves the interaction of multiple genetic and environmental factors such as salt intake. Salt-inducible kinase 1 (SIK1) is a sucrose-nonfermenting-like kinase isoform that belongs to the AMPK (5′ adenosine monophosphate-activated protein kinase) family. SIK1 activity is increased by high salt intake and plays an essential role in regulating the plasma membrane Na+,K+-ATPase. The objective of this study was to examine whether SIK1 is present in vascular smooth muscle cells (VSMCs) and endothelial cells, whether it affects VSMC Na+,K+-ATPase activity and whether human SIK1 (hSIK1) represents a potential candidate for blood pressure regulation.Localization of SIK1 was performed using immunohistochemistry, mRNA and western blot. Functional assays (Na+,K+-ATPase activity) were performed in VSMCs derived from rat aorta. Genotype–phenotype association studies were performed in three Swedish and one Japanese population-based cohorts.SIK1 was localized in human VSMCs and endothelial cells, as well as a cell line derived from rat aorta. A nonsynonymous single nucleotide polymorphism in the hSIK1 gene exon 3 (C→T, rs3746951) results in the amino acid change 15Gly→Ser in the SIK1 protein. SIK1-15Ser was found to increase plasma membrane Na+,K+-ATPase activity in cultured VSMC line from rat aorta. Genotype–phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that T allele (coding for 15Ser) was associated with lower blood pressure (P = 0.005 for SBP and P = 0.002 for DBP) and with a decrease in left ventricular mass (P = 0.048).The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.