High-Glucose-Derived Oxidative Stress-Dependent Heme Oxygenase-1 Expression from Astrocytes Contributes to the Neuronal Apoptosis

An elevated level of glucose has been found in the blood of hyperglycemia and diabetes patients associated with several central nervous system (CNS) complications. These disorders may be due to the up-regulation of many neurotoxic mediators by host cells triggered by high glucose (HG). Moreover, heme oxygenase-1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. However, the molecular mechanisms underlying HG-induced HO-1 expression in brain cells remain poorly defined. Thus, we use the rat brain astrocytes (RBA-1) as a model to investigate the signaling mechanisms of HO-1 induction by HG and its effects on neuronal cells. We demonstrated that HG induced HO-1 expression via a reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)- and mitochondrion-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream transcriptional factors nuclear factor-kappaB (NF-κB) and c-Fos/activator protein 1 (AP-1), respectively. Subsequently, the activated NF-κB and AP-1 turned on transcription of HO-1 gene. These results indicated that in brain astrocytes, activation of MAPK-mediated NF-κB and c-Fos/AP-1 cascades by Nox/ROS and mitoROS-dependent events is essential for HO-1 up-regulation induced by HG. Moreover, we found that HG-induced extracellular ROS increase and HO-1 expression from astrocytes resulted in neuronal apoptosis. These results offers new insights into the mechanisms and effects of the action of HG, supporting that HG may cause brain disorders in the development of diabetes- and hyperglycemia-induced CNS complications such as neurodegenerative diseases.