ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells

Exp Cell Res. 2005 Aug 15;308(2):291-9. doi: 10.1016/j.yexcr.2005.04.028.

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

  • Angiotensin II / metabolism*
  • Angiotensin II / pharmacology
  • Animals
  • Blood Vessels / metabolism*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Glucose / metabolism*
  • Glucose Transporter Type 4
  • Hypertension / physiopathology
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • JNK Mitogen-Activated Protein Kinases / drug effects
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Mitogen-Activated Protein Kinase 1 / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / drug effects
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Monosaccharide Transport Proteins / drug effects
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins / drug effects
  • Muscle Proteins / metabolism
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Serine / metabolism
  • Tyrosine / metabolism

Substances

  • Enzyme Inhibitors
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Slc2a4 protein, rat
  • Angiotensin II
  • Tyrosine
  • Serine
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Glucose