High glucose induces reactive oxygen species-dependent matrix metalloproteinase-9 expression and cell migration in brain astrocytes.

A rising level of glucose has been found in the blood of hyperglycemia and diabetes patients associated with brain inflammatory diseases. These diseases may be due to secretion of proinflammatory mediators by host cells triggered by high concentration of glucose. Moreover, increased plasma levels of matrix metalloproteinases (MMPs), MMP-9 especially, have been observed in patients with brain injuries and may contribute to brain inflammatory diseases. However, whether or not high glucose (HG) level triggers the central nervous system (CNS) inflammatory responses during hyperglycemia and diabetes are still unclear. In this study, we use a transformed astroglial cell (rat brain astrocyte-1; RBA-1) as a model to investigate regulatory mechanisms and roles of MMP-9 induction by HG in these cells. First, we demonstrated that HG upregulated MMP-9 gene expression by gelatin zymography, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analyses. Next, data obtained with selective pharmacological inhibitors and small interfering RNAs (siRNAs) showed that HG-induced MMP-9 expression is mediated through a c-Src-dependent reactive oxygen species (ROS) signal linking to activation of mitogen-activated protein kinases (MAPKs). Subsequently, the transcriptional factor nuclear factor-kappa B (NF-κB) was activated and thereby turned on transcription of MMP-9 gene. Functionally, HG-induced MMP-9 expression enhanced astrocyte migration. These results will provide new insights into the mechanisms of action of HG, supporting the hypothesis that HG may promote brain inflammation and remodeling in development of diabetes and hyperglycemia-induced CNS complications such as neurodegenerative diseases.