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

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, hyperos molarity, 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 cel ls (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 ma nnitol or tumor necrosis factor-alpha was not inhibited by GF109203X. Chang es in PKC isoform distribution after exposure to 16.5 mM glucose in SMC sug gested that both PKC-beta 2 and PKC-delta isoforms were increased. Activiti es of p38 kinase in PKC-delta- but not PKC-beta 1-overexpressed SMC were in creased compared with control cells. Activation of p38 kinase was also obse rved and characterized in various vascular cells in culture and aorta from diabetic rats. Thus, moderate hyperglycemia can activate p38 kinase by a PK C-delta isoform-dependent pathway, but glucose at extremely elevated levels can also activate p38 kinase by hyperosmolarity via a PKC-independent path way.