Abstract
Clinical evidence suggests a relationship between hypertension and insulin resistance, and cross-talk between angiotensin II (Ang II) and insulin signaling pathways may take place. We now report the effect of Ang II on insulin-induced glucose uptake and its intracellular mechanisms in vascular smooth muscle cells (VSMC). We examined the translocation of glucose transporter-4 (GLUT-4) and glucose uptake in rat aortic smooth muscle cells (RASMC). Mitogen-activated protein (MAP) kinases and Akt activities, and phosphorylation of insulin receptor substrate-1 (IRS-1) at the serine and tyrosine residues were measured by immunoprecipitation and immunoblotting. As a result, Ang II inhibited insulin-induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC. Ang II induced extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation and IRS-1 phosphorylation at Ser307 and Ser616. Ang II-induced Ser307 and Ser616 phophorylation of IRS-1 was inhibited by a MEK inhibitor, PD98059, and a JNK inhibitor, SP600125. Ang II inhibition of insulin-stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125. Ang II inhibited insulin-induced glucose uptake, which was also reversed by PD98059 but not by SP600125. It is shown that Ang II-induced ERK1/2 activation inhibits insulin-dependent glucose uptake through serine phophorylation of IRS-1 in RASMC.
MeSH terms
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Angiotensin II / metabolism*
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Angiotensin II / pharmacology
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Animals
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Blood Vessels / metabolism*
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Inhibitors / pharmacology
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Glucose / metabolism*
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Glucose Transporter Type 4
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Hypertension / physiopathology
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Insulin / metabolism*
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Insulin / pharmacology
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Insulin Receptor Substrate Proteins
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Insulin Resistance / physiology
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JNK Mitogen-Activated Protein Kinases / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Monosaccharide Transport Proteins / drug effects
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins / drug effects
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Muscle Proteins / metabolism
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism*
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport / drug effects
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Protein Transport / physiology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Serine / metabolism
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Tyrosine / metabolism
Substances
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Enzyme Inhibitors
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Glucose Transporter Type 4
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Insulin
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Insulin Receptor Substrate Proteins
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Irs1 protein, rat
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Monosaccharide Transport Proteins
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Muscle Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Slc2a4 protein, rat
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Angiotensin II
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Tyrosine
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Serine
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Glucose