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under hydrostatic pressure (Hernandez et al., 2000). In cultured human optic nerve astrocytes TGFb2 increased expression of collagen type 4 and transglutaminase 2 (Fuchshofer et al., 2005) so the alterations in TGFb2 levels and TGFb receptors noted above are consistent with enhanced expression of matrix protein. Interestingly, TGFb2 induces expression of TGM2 and fibronectin in cultured human trabecular meshwork cells (Zhao et al., 2004) and ECM proteins in organ culture. Therefore, alterations in TGFb signaling in POAG may affect not only the ONH but the aqueous outflow facility as well.

There are also alterations in the bone morphogenic protein (BMP) signaling pathways in glaucomatous astrocytes. BMPs are similar to TGFB in that the BMP receptors are coupled to SMAD proteins (SMAD1, SMAD4, SMAD5) and induce transcriptional activity (Zode et al., 2007). BMP4 is secreted by ONH astrocytes (Wordinger et al., 2002) and is upregulated 2.3-fold in cells from glaucoma donors (Hernandez et al., 2002). SMAD6 is one of the SMADs that inhibits the transcriptional activity of SMADs 1 and 4 (Chen et al., 2004). Expression of SMAD6 is upregulated in glaucomatous astrocytes (Hernandez et al., 2002) so that the elevated expression of BMP4 by glaucomatous ONH astrocytes may not affect these cells, but could affect the neighboring lamina cribrosa cells that also have BMP4 receptors (Zode et al., 2007).

Oxidative stress in ONH astrocytes

Hydrogen peroxide (H2O2), which is abundantly produced during CNS injury and ischemia, promotes pathological excitatory amino acid release and swelling of reactive astrocytes (Hirrlinger et al., 2000). The antioxidant glutathione (GSH) plays an important role in protecting the mitochondrial electron transport chain (ETC) from damage by oxidative stress in astrocytes and neurons. GSH represents the major CNS thiol and is essential for prevention of oxidative stress. In the CNS, astrocytes use either glutamate or glutamine as precursors for GSH synthesis. Damage to the axons of RGC in glaucoma may

occur by production of reactive oxygen species (ROS) by reactive astrocytes (Tezel, 2006). Our microarray data indicates that glaucomatous astrocytes may counteract the effects of ROS on RGC axons by increasing production of GSH through increased expression of glutamatecysteine ligase (GCL), the rate-limiting enzyme of the synthesis of GSH (Hernandez et al., 2002). GSH plays an important role in protecting the mitochondrial ETC from damage by oxidative stress in astrocytes and neurons. The antioxidant enzyme mitochondrial superoxide dismutase (SOD2) catalyzes the dismutation reaction involving the conversion of superoxide anion (O2 ) to oxygen (O2) and H2O2. Data from our laboratory shows that in glaucomatous astrocytes increased SOD2 expression (Fig. 8) is under transcriptional regulation of NF-kB via the androgen receptor (AR) (Agapova et al., 2006b).

Human OHN astrocytes treated with HNE showed immediate decreased cellular levels of GSH, which in turn induced expression of GCLC, the rate-limiting enzyme in the synthesis of GSH (Malone and Hernandez, 2007). The strong induction of GCLC and new synthesis of GSH after a 24 h recovery from the HNE treatment indicates that ONH astrocytes can manage oxidative stress. These results are consistent with similar experiments performed with Madin-Darby canine kidney II cells (MDCK II) (Ji et al., 2004), transformed human bronchial epithelial (HBE1) cells (Dickinson et al., 2002), and rat astrocytes (Ahmed et al., 2002).

Glaucomatous ONH astrocytes compared to normal ONH astrocytes have lower basal levels of GSH, which may imply a compromised oxidation– reduction system or a depleted antioxidant response in the glaucomatous optic nerve (Malone and Hernandez, 2007). This observation is consistent with a study that assessed the levels of plasma GSH in patients with untreated POAG and found lower levels of circulating GSH in glaucoma patients when compared to control subjects (Gherghel et al., 2005). However, unlike the normal ONH astrocytes, glaucomatous ONH astrocytes exhibited increased levels of GSH immediately following treatment with HNE. This result may be consistent with findings by Ferreira

(Ferreira et al., 2004) who found 3-fold higher glutathione peroxidase activity in the aqueous humor of patients with glaucoma compared to patients with cataracts. This is further evidence of alterations in antioxidant enzymes in glaucoma.

AKR1C1, an aldo–keto reductase involved in androgen and neurosteroid metabolism, has been shown to be over-expressed in glaucomatous optic nerves, suggesting a constitutive response to chronic oxidative stress (Agapova et al., 2003b). ONH

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astrocytes upregulate expression AKR1C1 following treatment with HNE, which can inactivate HNE. AKR1C1 acts as a reductase by converting HNE to 1,4-dihydroxy-2-nonene (an inactive metabolite), thereby eliminating the ability of HNE to bind to protein or DNA (Burczynski et al., 2001). Enzymes such as AKR1C1 may play a more important role in the inactivation of HNE when the primary stores of GSH are depleted in the cell, as exhibited immediately following treatment with HNE in normal ONH astrocytes, because AKR1C1 can reduce HNE independent of GSH.

Glial cells protect neurons and are involved in the antioxidant defense in the brain by synthesizing GSH, mostly located in glial cells in the brain (Pearce et al., 1997) and by providing precursors that neurons require to make their own GSH (Sagara et al., 1993; Dringen et al., 1999). Since astrocytes have high levels of antioxidants (Makar et al., 1994; Dringen and Hamprecht, 1997), they can sustain the presence of ROS and therefore prevent their neurotoxicity (Wilson, 1997) which we demonstrated after HNE treatment.

Astrocytes can transport GSH conjugated to HNE out of the cell via the multidrug-resistance protein (MRP1) (Hirrlinger et al., 2002) or through the RLIP76 (Ral binding protein) (Yang et al., 2003). Once outside of the cell, the released GSH cannot be taken up by neurons, so gamma-glutamyl transpeptidase (GGT) present on the plasma membrane of astrocytes cleaves GSH into components that can be further cleaved and taken up by neurons. These basic components are then utilized by the neuron to synthesize GSH (Heales et al., 2004). Therefore, ONH astrocytes may offer neuroprotection in the optic nerve by releasing GSH and antioxidant enzymes to eliminate the products of chronic oxidative stress that may be contributing to the progression of neurodegeneration in POAG.

Conclusions

This review intends to raise many questions that will require future investigations. Astrocytes serve protective and trophic functions to the axons of the retinal ganglion cells in the optic nerve.

Glaucomatous ONH astrocytes share many characteristics of reactive astrocytes in the CNS; certain properties may be specific to the pathophysiology of glaucoma. Our own data indicates that the microenvironment supported by astrocytes in the normal and glaucomatous ONH has characteristics that may impact susceptibility to glaucomatous optic neuropathy in certain individuals. Future directions include identification and characterization of signaling pathways involved in astrocyte function and further exploration on the role of selected identified genes in experimental animal and in vitro models of glaucoma.

Acknowledgments

This work was supported by National Institutes of Health Grant EY-06416 and by National Research to Prevent Blindness (RPB).

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