Involvement of oxidative stress and mitochondrial dysfunction in the osmotic swelling of retinal glial cells from diabetic rats

Krügel, Katja; Wurm, Antje; Pannicke, Thomas; Hollborn, Margrit; Karl, Anett; Wiedemann, Peter; Reichenbach, Andreas; Kohen, Leon; Bringmann, Andreas

doi:10.1016/j.exer.2010.11.007

Cited by 38 publications

(24 citation statements)

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“…7). Additionally, activation of P2Y receptors has been shown to regulate osmotic changes within the diseased and damaged retina and may be linked to fluxes of Ca 2ϩ or other ions that modulate caspase activity (6,14,24,48,50). However, exogenous UTP, which also triggered robust Ca 2ϩ mobilization (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…2A). Multiple reports have described the expression of functional adenosine receptors in retinal Müller cells (24,49). Our findings represent the first linkage of these G protein-coupled receptors to caspase-1 based inflammation and support a model wherein A2 adenosine receptors, coupled to cAMP signaling, induce transcriptional upregulation of caspase-1 and TXNIP, a glucose-sensitive adapter protein linked to caspase-1 activation.…”

Section: Discussionmentioning

confidence: 99%

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Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1

Trueblood

Mohr

Dubyak

2011

American Journal of Physiology-Cell Physiology

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Trueblood KE, Mohr S, Dubyak GR. Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1. Am J Physiol Cell Physiol 301: C1213-C1223, 2011. First published August 10, 2011; doi:10.1152/ajpcell.00265.2011.-Chronic activation of proinflammatory caspase-1 in the retinas of diabetic animals and patients in vivo and retinal Müller cells in vitro is well documented. In this study we characterized how elevated glucose and extracellular purines contribute to the activation of caspase-1 in a cultured rat Müller cell (rMC-1) model. The ability of high glucose (25 mM, 24 h) to activate caspase-1 was attenuated by either apyrase, which metabolizes extracellular ATP to AMP, or adenosine deaminase (ADA), which metabolizes extracellular adenosine to inosine. This suggested that autocrine stimulation of ATPsensing P2 receptors and adenosine-sensing P1 receptors may in part mediate the response to high glucose. Exogenous ATP, 5=-N-ethylcarboxamido-adenosine (NECA), a nonselective P1 receptor agonist, or forskolin (FSK) increased caspase-1 activity in rMC-1 cells cultured in control glucose (5 mM) medium. Accumulation of active caspase-1 was also increased by dipyridamole, which suppresses adenosine reuptake. High-glucose stimulation of caspase-1 was attenuated by suramin, a nonselective P2 antagonist, or A2 adenosine receptor antagonists, but not by antagonism of P2X7 ATP-gated ion channel receptors. Although high glucose increased P2X7 mRNA, neither P2X7 protein nor function was detected in rMC-1 cells. The increased caspase-1 activity stimulated by high glucose, FSK, NECA, or ATP was correlated with increased gene expression of caspase-1 and thioredoxin-interacting-protein (TXNIP). These findings support a novel role for autocrine P1 and P2 purinergic receptors coupled to cAMP signaling cascades and transcriptional induction of caspase-1 in mediating the high-glucose-induced activation of caspase-1 and secretion of IL-1␤ in a cell culture model of nonhematopoietic retinal Müller cells. sterile inflammation; hyperglycemia; inflammasome; purinergic signaling DIABETIC RETINOPATHY, a chronic, sterile inflammatory condition, is characterized by increased levels of active caspase-1 and interleukin-1-␤ (IL-1␤), which are strongly implicated in retinal degeneration (11,15,22,31,44). One source of active caspase-1 and IL-1␤ are retinal Müller cells which, as the principal glia of the retina, provide vital structural and metabolic support to retinal neurons (5, 53, 54). As such, it has been postulated that inflammatory activation, characterized by increased caspase-1/IL-1␤ signaling and mitochondrial stress, of Müller cells under hyperglycemic conditions contributes to the development and progression of the disease (31, 44). We and others have previously reported that inhibition of caspase-1/ interleukin-1␤ signaling prevents degeneration of retinal capillaries in diabetes (11,15,22,31,44). Our more recent studies have demonstrated that a vicious cycle of autocrine activation of caspa...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1

Trueblood

Mohr

Dubyak

2011

American Journal of Physiology-Cell Physiology

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“…49 This suggests that the neuroprotective effect provided by cyclosporin A that has been used previously to treat rats with diabetic retinopathy 50 and that can prevent the loss of therapeutic cell transplants from dying in the retina 51 could be in part the result of inhibiting RIP3-dependent necroptosis rather than due to its immunosuppressive activity alone.…”

Section: Discussionmentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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“…2E), retinal vein occlusion, ocular inflammation, retinal detachment (Fig. 3J), blue light-induced retinal degeneration, and inherited photoreceptor degeneration, as well as in the detached human retina (Pannicke et al, 2004Uckermann et al, 2005cUckermann et al, , 2006Weuste et al, 2006;Wurm et al, 2006Wurm et al, , 2008a2011b;Iandiev et al, 2006Iandiev et al, , 2008Rehak et al, 2009;Krügel et al, 2010Krügel et al, , 2011Grosche et al, 2012). The loss of the cell volume control was suggested to be caused by the downregulation of functional Kir4.1 channels (Fig.…”

Section: Dysregulation Of Glial Homeostatic Functionsmentioning

confidence: 95%