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Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways
Masahiko Igarashi, … , Christopher J. Rhodes, George L. King
Masahiko Igarashi, … , Christopher J. Rhodes, George L. King
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):185-195. https://doi.org/10.1172/JCI3326.
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Article

Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways

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Abstract

Hyperglycemia can cause vascular dysfunctions by multiple factors including hyperosmolarity, oxidant formation, and protein kinase C (PKC) activation. We have characterized the effect of hyperglycemia on p38 mitogen-activated protein (p38) kinase activation, which can be induced by oxidants, hyperosmolarity, and proinflammatory cytokines, leading to apoptosis, cell growth, and gene regulation. Glucose at 16.5 mM increased p38 kinase activity in a time-dependent manner compared with 5.5 mM in rat aortic smooth muscle cells (SMC). Mannitol activated p38 kinase only at or greater than 22 mM. High glucose levels and a PKC agonist activated p38 kinase, and a PKC inhibitor, GF109203X, prevented its activation. However, p38 kinase activation by mannitol or tumor necrosis factor-α was not inhibited by GF109203X. Changes in PKC isoform distribution after exposure to 16.5 mM glucose in SMC suggested that both PKC-β2 and PKC-δ isoforms were increased. Activities of p38 kinase in PKC-δ– but not PKC-β1–overexpressed SMC were increased compared with control cells. Activation of p38 kinase was also observed and characterized in various vascular cells in culture and aorta from diabetic rats. Thus, moderate hyperglycemia can activate p38 kinase by a PKC-δ isoform–dependent pathway, but glucose at extremely elevated levels can also activate p38 kinase by hyperosmolarity via a PKC-independent pathway.

Authors

Masahiko Igarashi, Hisao Wakasaki, Noriko Takahara, Hidehiro Ishii, Zhen-Y Jiang, Teruaki Yamauchi, Koji Kuboki, Matthias Meier, Christopher J. Rhodes, George L. King

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Figure 6

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Effect of PKC-β1 overexpression on p38 MAP kinase in rat aortic SMC. (a)...
Effect of PKC-β1 overexpression on p38 MAP kinase in rat aortic SMC. (a) Characterization of PKC-β1 overexpression in rat aortic SMC after adenovirus infection. (1) Total cell lysate was isolated from cells that were not infected (cont.), or infected with Adv-CMV-βGal (β-gal) or Adv-CMV-PKC-β1 (PKC-β1). PKC-β1 protein was detected by immunoblot analysis. (2) Four days after infection with adenovirus, cells were lysed and the cytosol and membrane proteins were fractionated by ultracentrifugation. The PKC activity was measured as described in Methods. Each bar represents the mean + SD (n = 5). *P < 0.001 vs. noninfected and β-gal. (b) Activation of p38 MAP kinase in PKC-β1–overexpressed SMC. Four days after infection with adenovirus, total cell lysate was isolated. The samples were separated by 10% SDS-gel, and the phosphorylation of p38 MAP kinase was detected by immunoblot analysis using phosphospecific p38 MAP kinase as described in Methods. The results were derived from three separate experiments.

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