Angiotensin II inhibits insulin-induced actin stress fiber formation and glucose uptake via ERK1/2.
There is crosstalk in intracellular signaling between Angiotensin II (Ang II) and insulin. We hypothesized that the underlying mechanism might be related to changes in cytoskeleton. In the presence of 100 nM of Ang II, insulin-induced glucose uptake was decreased and insulin-induced actin filament organization was inhibited. PKC inhibitors, including GF109203x and p38MAPK inhibitor (SB203580) neither improved insulin-induced actin reorganization nor glucose uptake. In contrast, the Ang II-induced inhibition of glucose uptake and actin filament disorganization was reversed by 10 micromol ERK 1/2 MAPK inhibitor (PD98059). Pretreatment of Ang II increased ERK1/2 phosphorylation and inhibited insulin-induced Akt phosphorylation. The effect of Ang II on ERK1/2 phosphorylation was blocked by Ang II type 1 receptor antagonists, RNH6270 and PD98059 but not by SB203580 or Guanosine-5'-O-(2-ThioDiphosphate), a G-protein inhibitor. We next tested the effect of broad-spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) on Ang II-inhibition of insulin signaling pathway. GM6001 did not improve Ang II-induced actin filament disorganization and did not inhibit ERK1/2 phosphorylation. From these data in L6 myotube, we conclude that Ang II negatively regulates the insulin signal not through MMP signaling pathway but specifically through MMP-independent ERK1/2 activation pathway, providing an alternative molecular mechanism for angiotensin-induced insulin resistance.
Nazari
Hossein
H
Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Takahashi
Akira
A
Harada
Nagakatsu
N
Mawatari
Kazuaki
K
Nakano
Masayuki
M
Kishi
Kazuhiro
K
Ebina
Yousuke
Y
Nakaya
Yutaka
Y
D000804:Angiotensin II / Q000494:pharmacology*; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D022502:Stress Fibers / Q000187:drug effects* / Q000502:physiology
D007328:Insulin; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose