title: Increased arterial blood pressure and vascular remodeling in mice lacking salt-inducible kinase 1 (SIK1).
abstract: BACKGROUND
  In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes.
  
  
  OBJECTIVE
  To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure.
  
  
  RESULTS
  SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal- or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1(+/+) mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs.
  
  
  CONCLUSIONS
  Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-β1-signaling inhibition.
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Bertorello
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Nuno
authors.initials: N
authors.lastname: Pires
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Bruno
authors.initials: B
authors.lastname: Igreja
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Pinho
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Emina
authors.initials: E
authors.lastname: Vorkapic
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Wikström
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Margareta
authors.initials: M
authors.lastname: Behrendt
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.).
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
authors.affiliation: From the Department of Medicine, Membrane Signaling Networks, Karolinska Institutet, Stockholm, Sweden (A.M.B., L.B.); Department of Research and Development, Bial-Portela & Cª, S.A., S. Mamede do Coronado, Portugal (N.P., B.I., P.S.-d.-S.); MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal (M.J.P., P.S.-d.-S.); Department of Medicine, Cardiovascular Genetics and Genomics, Karolinska Institutet, Stockholm, Sweden (E.V., D.W., A.H., P.E.); Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden (E.V., D.W.); and Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (J.W., M.B.). laura.brion@ki.se.
authors.forename: Laura
authors.initials: L
authors.lastname: Brion
mesh_terms: D063194:Adventitia / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D062186:Arterial Pressure; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D009318:Natriuresis; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary; D013564:Sympathetic Nervous System / Q000503:physiopathology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D066253:Vascular Remodeling; D014661:Vasoconstriction
chemical_list: D019332:Endothelin-1; D017673:Sodium Chloride, Dietary; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C495376:Sik1 protein, mouse
keywords: SIK1 protein, human; endothelin-1; muscle, smooth, vascular; vascular remodeling