Salt-inducible kinase 1 influences Na+,K+-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure

Sergej Popov, Angela Silveira, Dick Wågsäter, Hiroshi Takemori, Ryousuke Oguro, Sachiko Matsumoto, Ken Sugimoto, Kei Kamide, Takuo Hirose, Michihiro Satoh, Hirohito Metoki, Masahiro Kikuya, Takayoshi Ohkubo, Tomohiro Katsuya, Hiromi Rakugi, Yutaka Imai, Fabio Sanchez, Margret Leosdottir, Ann Christine Syvänen, Anders HamstenOlle Melander, Alejandro M. Bertorello

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 Gly→Ser in the SIK1 protein. SIK1-Ser 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 Ser) 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). CONCLUSION: The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.

Original languageEnglish
Pages (from-to)2395-2403
Number of pages9
JournalJournal of hypertension
Volume29
Issue number12
DOIs
Publication statusPublished - 2011 Dec

Keywords

  • Hypertension
  • salt sensitivity
  • vascular tonus

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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