Differential neuronal expression of receptor interacting protein 3 in rat retina: involvement in ischemic stress response

Huang, Jufang; Shang, Lei; Zhang, Mengqi; Wang, Hui J.; Chen, Dan; Tong, Jianbin; Huang, He; Yan, Xiao‐Xin; Zeng, Leping; Xiong, Kun

doi:10.1186/1471-2202-14-16

Cited by 52 publications

(38 citation statements)

References 33 publications

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“…Our data suggest that the Ripk1 and Ripk3 proteins, which are required to initiate necroptosis (Degterev and Yuan, 2008; Galluzzi and Kroemer, 2008; Takahashi et al, 2012; Vandenabeele et al, 2010), are present in control and ischemic RGCs. It should be noted that the pattern of Ripk3 protein distribution in sham-operated and IR mouse retinas coincides with Ripk3 protein distribution in sham-operated and ischemic rat retinas (Huang et al, 2013). We found that inhibiting the activation of the Ripk1/Ripk3-pathway in RGCs, using Nec1, significantly reduced IR-induced retinal damage.…”

Section: Discussionmentioning

confidence: 71%

Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia–reperfusion-induced retinal damage

Dvoriantchikova

Degterev

Ivanov

2014

Experimental Eye Research

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Retinal ischemia–reperfusion (IR) injury remains a common cause of blindness and has a final pathway of retinal ganglion cell (RGC) death by apoptosis and necrosis. RGC apoptosis was intensively studied in IR injury, while RGC necrosis did not receive nearly enough consideration since it was viewed as an accidental and unregulated cellular event. However, there is evidence that necrosis, like apoptosis, can be implemented by a programmed mechanism. In this study, we tested the role of RGC programmed necrosis (necroptosis) in IR-induced retinal injury. We employed the mouse model of retinal IR injury for in vivo experiments. The oxygen and glucose deprivation (OGD) model was used as an IR model in vitro. Primary RGCs were isolated by an immunopanning technique. Necrostatin 1 (Nec1) was used to inhibit necroptosis in in vitro and in vivo experiments. The changes in gene expression were assessed by quantitative RT-PCR. The distribution of proteins in the retina and in RGC cultures was evaluated by immunohistochemistry and immunocytochemistry, respectively. Our data suggest that proteins (Ripk1 and Ripk3), which initiate necroptosis, were present in normal and ischemic RGCs. Treatment with Nec1 significantly reduced retinal damage after IR. Increased RGC survival and reduced RGC necrosis following OGD were observed in Nec1-treated cultures. We found significantly reduced expression of genes coding pro-inflammatory markers Il1b, Ccl5, Cxcl10, Nos2 and Cybb in Nec1-treated ischemic retinas. Thus, our findings suggest that RGC necroptosis contributes to retinal damage after IR through direct loss of cells and induction of associated inflammatory responses.

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Section: Discussionmentioning

confidence: 71%

Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia–reperfusion-induced retinal damage

Dvoriantchikova

Degterev

Ivanov

2014

Experimental Eye Research

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“…Previous studies have reported that RIP-3 expression is rapidly increased in cells of the GCL and INL in the rat retina following acute increases in intraocular pressure (IOP). 54 It was also reported that RIP-3 immunolabeling was colocalized with the PI-positive cells in the GCL that indicates the involvement of RIP-3 in necroptotic cell death. Our western blotting analysis showed a significant increase in RIP-3 protein expression following I/R, which was significantly reduced in A2-deficient retinas.…”

Section: Discussionmentioning

confidence: 89%

Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury

Shosha

Yokota

et al. 2016

Cell Death Dis

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Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies. Here, we are introducing A2 as a therapeutic target to prevent neurovascular injury after retinal ischemia/reperfusion (I/R) insult. Studies were performed with mice lacking both copies of A2 (A2−/−) and wild-type (WT) controls (C57BL6J). I/R insult was conducted on the right eye and the left eye was used as control. Retinas were collected for analysis at different times (3 h–4 week after injury). Neuronal and microvascular degeneration were evaluated using NeuN staining and vascular digests, respectively. Glial activation was evaluated by glial fibrillary acidic protein expression. Necrotic cell death was studied by propidium iodide labeling and western blot for RIP-3. Arginase expression was determined by western blot and quantitative RT-PCR. Retinal function was determined by electroretinography (ERG). A2 mRNA and protein levels were increased in WT I/R. A2 deletion significantly reduced ganglion cell loss and microvascular degeneration and preserved retinal morphology after I/R. Glial activation, reactive oxygen species formation and cell death by necroptosis were significantly reduced by A2 deletion. ERG showed improved positive scotopic threshold response with A2 deletion. This study shows for the first time that neurovascular injury after retinal I/R is mediated through increased expression of A2. Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R.

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“…174,175 In one study, the death-associated protein DAXX was suggested to be a critical downstream target of RIPK3, 175 although this has not been confirmed in this or any other system. 174,175 In one study, the death-associated protein DAXX was suggested to be a critical downstream target of RIPK3, 175 although this has not been confirmed in this or any other system.…”

Section: Ophthalmology and Necroptosismentioning

confidence: 95%

The in vivo evidence for regulated necrosis

Tonnus

Linkermann

2017

Immunological Reviews

103

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Necrosis is a hallmark of several widespread diseases or their direct complications. In the past decade, we learned that necrosis can be a regulated process that is potentially druggable. RIPK3- and MLKL-mediated necroptosis represents by far the best studied pathway of regulated necrosis. During necroptosis, the release of damage-associated molecular patterns (DAMPs) drives a phenomenon referred to as necroinflammation, a common consequence of necrosis. However, most studies of regulated necrosis investigated cell lines in vitro in a cell autonomous manner, which represents a non-physiological situation. Conclusions based on such work might not necessarily be transferrable to disease states in which synchronized, non-cell autonomous effects occur. Here, we summarize the current knowledge of the pathophysiological relevance of necroptosis in vivo, and in light of this understanding, we reassess the morphological classification of necrosis that is generally used by pathologists. Along these lines, we discuss the paucity of data implicating necroptosis in human disease. Finally, the in vivo relevance of non-necroptotic forms of necrosis, such as ferroptosis, is addressed.

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Differential neuronal expression of receptor interacting protein 3 in rat retina: involvement in ischemic stress response

Cited by 52 publications

References 33 publications

Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia–reperfusion-induced retinal damage

Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia–reperfusion-induced retinal damage

Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury

The in vivo evidence for regulated necrosis

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