Endogenous tissue type plasminogen activator facilitates NMDA-induced retinal damage

Kumada, Masako; Niwa, Masayuki; Wang, Xiaodan; Matsuno, Hiroyuki; Hara, Akira; Mori, Hideki; Matsuo, Osamu; Yamamoto, Tetsuya; Kozawa, Osamu

doi:10.1016/j.taap.2004.03.017

Cited by 13 publications

(8 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TUNEL-positive signals increased from 12 hr and peaked at D1 followed by rapid reduction at D3 and backed to the control level at D7 (Figure 8a,b), highly correspondent to previous reports Kumada et al, 2004;Kwong et al, 2003;Kwong & Lam, 2000;Zhang et al, 2008) and the pattern for Tnfa expression. Because proinflammatory cytokine-mediated neuronal death is usually caused by rapid action, we re-evaluated RGC damages by TUNEL.…”

Section: Rgc Damages Occur In Temporal Pattern Similar To Tnfα Exprsupporting

confidence: 91%

“…Because proinflammatory cytokine-mediated neuronal death is usually caused by rapid action, we re-evaluated RGC damages by TUNEL. TUNEL-positive signals increased from 12 hr and peaked at D1 followed by rapid reduction at D3 and backed to the control level at D7 (Figure 8a,b), highly correspondent to previous reports Kumada et al, 2004;Kwong et al, 2003;Kwong & Lam, 2000;Zhang et al, 2008) and the pattern for Tnfa expression. TUNEL signals were co-localized with pyknotic nuclei-like Brn3a signals (arrows in Figure 8c) but not with large Brn3a signals (asterisks in Figure 8c).…”

Section: Rgc Damages Occur In Temporal Pattern Similar To Tnfα Exprsupporting

confidence: 91%

See 1 more Smart Citation

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Takeda

Shinozaki

Kashiwagi

et al. 2018

Glia

View full text Add to dashboard Cite

Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1‐tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up‐regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up‐regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA‐induced degeneration of RGCs, suggesting an importance of non‐cell‐autonomous mechanism in the retinal neuronal excitotoxicity.

show abstract

Section: Rgc Damages Occur In Temporal Pattern Similar To Tnfα Exprsupporting

confidence: 91%

Section: Rgc Damages Occur In Temporal Pattern Similar To Tnfα Exprsupporting

confidence: 91%

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Takeda

Shinozaki

Kashiwagi

et al. 2018

Glia

View full text Add to dashboard Cite

show abstract

“…In contrast, reactive astrocytes in the retina express increased levels of MMP-9 and uPA [19], degrade the extracellular matrix in the inner limiting membrane, and promote death of RGCs by detachment-induced apoptosis [17], [30]. In support of the detrimental role of astrocytes, we and others have shown that a deficiency of either MMP-9 [30] or tPA [31] attenuates RGC death significantly.…”

Section: Discussionmentioning

confidence: 65%

Inhibition of Reactive Gliosis Attenuates Excitotoxicity-Mediated Death of Retinal Ganglion Cells

Ganesh

Chintala

2011

PLoS ONE

View full text Add to dashboard Cite

Reactive gliosis is a hallmark of many retinal neurodegenerative conditions, including glaucoma. Although a majority of studies to date have concentrated on reactive gliosis in the optic nerve head, very few studies have been initiated to investigate the role of reactive gliosis in the retina. We have previously shown that reactive glial cells synthesize elevated levels of proteases, and these proteases, in turn, promote the death of retinal ganglion cells (RGCs). In this investigation, we have used two glial toxins to inhibit reactive gliosis and have evaluated their effect on protease-mediated death of RGCs. Kainic acid was injected into the vitreous humor of C57BL/6 mice to induce reactive gliosis and death of RGCs. C57BL/6 mice were also treated with glial toxins, alpha-aminoadipic acid (AAA) or Neurostatin, along with KA. Reactive gliosis was assessed by immunostaining of retinal cross sections and retinal flat-mounts with glial fibrillary acidic protein (GFAP) and vimentin antibodies. Apoptotic cell death was assessed by TUNEL assays. Loss of RGCs was determined by immunostaining of flat-mounted retinas with Brn3a antibodies. Proteolytic activities of matrix metalloproteinase-9 (MMP-9), tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) were assessed by zymography assays. GFAP-immunoreactivity indicated that KA induced reactive gliosis in both retinal astrocytes and in Muller cells. AAA alone or in combination with KA decreased GFAP and vimentin-immunoreactivity in Mϋller cells, but not in astrocytes. In addition AAA failed to decrease KA-mediated protease levels and apoptotic death of RGCs. In contrast, Neurostatin either alone or in combination with KA, decreased reactive gliosis in both astrocytes and Mϋller cells. Furthermore, Neurostatin decreased protease levels and prevented apoptotic death of RGCs. Our findings, for the first time, indicate that inhibition of reactive gliosis decreases protease levels in the retina, prevents apoptotic death of retinal neurons, and provides substantial neuroprotection.

show abstract

“…The mechanisms by which secreted proteases, tPA and uPA, directly cause death of RGCs are unclear, although previous studies from our laboratory (Zhang, et al, 2003) and other laboratories (Kumada, et al, 2005, Kumada, et al, 2004 have provided evidence elevated levels of these proteases cause death of RGCs in vivo (Mali, et al, 2005) and RGC-5 cells in vitro (Harvey and Chintala, 2007). In this study, we provide further evidence that tPA and uPA dictate the survival of RGC-5 cells, in part, by interacting with LRP-1.…”

Section: Discussionmentioning

confidence: 92%

Mechanisms regulating plasminogen activators in transformed retinal ganglion cells

Rock¹,

Chintala²

2008

Experimental Eye Research

View full text Add to dashboard Cite

Irreversible loss of retinal ganglion cells (RGCs) is a major clinical issue in glaucoma, but the mechanisms that lead to RGC death are currently unclear. We have previously reported that elevated levels of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) cause the death of RGCs in vivo and transformed retinal ganglion cells (RGC-5) in vitro. Yet, it is unclear how secreted proteases such as tPA and uPA directly cause RGCs' death. In this study, by employing RGC-5 cells, we report that tPA and uPA elicit their direct effect through the low-density lipoprotein-related receptor-1 (LRP-1). We also show that blockade of protease-LRP-1 interaction leads to a complete reduction in autocrine synthesis of tPA and uPA, and prevents protease-mediated death of RGC-5 cells. RGC-5 cells were cultured in serum-free medium and treated with 2.0 microM Staurosporine to induce their differentiation. Neurite outgrowth was observed by a phase contrast microscope and quantified by NeuroJ imaging software. Proteolytic activities of tPA and uPA were determined by zymography assays. Cell viability was determined by MTT assays. Compared to untreated RGC-5 cells, cells treated with Staurosporine differentiated, synthesized and secreted elevated levels of tPA and uPA, and underwent cell death. In contrast, when RGC-5 cells were treated with Staurosporine along with the receptor associated protein (RAP), proteolytic activities of both tPA and uPA were significantly reduced. Under these conditions, a significant number of RGC-5 cells survived and showed increased neurite outgrowth. These results indicate that LRP-1 regulates autocrine synthesis of tPA and uPA in RGC-5 cells and suggest that the use of RAP to antagonize the effect of proteases may be a way to prevent RGC death in glaucoma.

show abstract

Endogenous tissue type plasminogen activator facilitates NMDA-induced retinal damage

Cited by 13 publications

References 19 publications

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

Inhibition of Reactive Gliosis Attenuates Excitotoxicity-Mediated Death of Retinal Ganglion Cells

Mechanisms regulating plasminogen activators in transformed retinal ganglion cells

Contact Info

Product

Resources

About