Retina-specific activation of a sustained hypoxia-like response leads to severe retinal degeneration and loss of vision

Lange, Christina; Caprara, Christian; Tanimoto, Naoyuki; Beck, Susanne; Huber, Günter L.; Samardzija, Marijana; Seeliger, Mathias W.; Grimm, Christian

doi:10.1016/j.nbd.2010.08.028

Cited by 20 publications

(27 citation statements)

References 47 publications

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“…This indicates that other Vhl-regulated downstream molecules, such as Hif2a, may be responsible for Vegf expression in the RPE, the secondary increase of angiogenic factors in the neuroretina and the associated vascular phenotype. Retina-specific inactivation of Vhl leads to a similar but milder vascular phenotype, including the persistence of hyaloid vasculature and the pupillary membrane (Kurihara et al, 2010;Lange et al, 2011). In contrast to our results, Kurihara et al reported that a combined inactivation of Vhl and Hif1a in the neuroretina rescues the vascular phenotype, suggesting that the observed phenotype was Hif1a mediated.…”

Section: Research Articlecontrasting

confidence: 95%

“…Our results demonstrate that conditional inactivation of Vhl in the RPE is associated with Hif1a-dependent increased apoptosis of RPE and pigmented iris cells. This finding is consistent with the results of recent studies showing that conditional inactivation of Vhl in the neuroretina is associated with increased apoptosis of photoreceptor cells (Kurihara et al, 2010;Lange et al, 2011). Hif1a regulates not only survival genes via its control of cellular proliferation and metabolism, vasomotor control and angiogenesis (Sharp and Bernaudin, 2004), but also the expression of proapoptotic factors.…”

Section: Research Articlesupporting

confidence: 92%

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Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development

et al. 2012

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SUMMARYMolecular oxygen is essential for the development, growth and survival of multicellular organisms. Hypoxic microenvironments and oxygen gradients are generated physiologically during embryogenesis and organogenesis. In the eye, oxygen plays a crucial role in both physiological vascular development and common blinding diseases. The retinal pigment epithelium (RPE) is a monolayer of cells essential for normal ocular development and in the mature retina provides support for overlying photoreceptors and their vascular supply. Hypoxia at the level of the RPE is closely implicated in pathogenesis of age-related macular degeneration. Adaptive tissue responses to hypoxia are orchestrated by sophisticated oxygen sensing mechanisms. In particular, the von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (HIF)-mediated adaptation. However, the role of Vhl/Hif1a in the RPE in the development of the eye and its vasculature is unknown. In this study we explored the function of Vhl and Hif1a in the developing RPE using a tissue-specific conditional-knockout approach. We found that deletion of Vhl in the RPE results in RPE apoptosis, aniridia and microphthalmia. Increased levels of Hif1a, Hif2a, Epo and Vegf are associated with a highly disorganised retinal vasculature, chorioretinal anastomoses and the persistence of embryonic vascular structures into adulthood. Additional inactivation of Hif1a in the RPE rescues the RPE morphology, aniridia, microphthalmia and anterior vasoproliferation, but does not rescue retinal vasoproliferation. These data demonstrate that Vhldependent regulation of Hif1a in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas Vhl-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature.KEY WORDS: Von Hippel-Lindau factor, Hypoxia-inducible factor 1, Microphthalmia, Angiogenesis, Mouse

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Section: Research Articlecontrasting

confidence: 95%

Section: Research Articlesupporting

confidence: 92%

Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development

et al. 2012

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“…Knockdown of the von Hippel-Lindau (VHL) protein during retinal development led to the activation of HIF1 and -2 and to increased Vegf expression. 19,20 Whereas the simultaneous knockdown of Vhl and Hif1a also led to increased VEGF levels, simultaneous ablation of Vhl and Epas1 (Hif2a) did not. 18 Furthermore, functional studies in a mutant cell line expressing neither HIF1A nor EPAS1 showed stronger transactivation of the VEGF promoter by EPAS1.…”

Section: Discussionmentioning

confidence: 98%

HIF1A Is Essential for the Development of the Intermediate Plexus of the Retinal Vasculature

Caprara¹,

Thiersch²,

Lange³

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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“…The retina has been used as an in vivo model for studying neuron stress and/or death in the central nervous system [13,20-23]. Also, retinal neuronal degeneration itself is characterized in many clinical conditions that can lead to blindness [24]. Understanding the molecular mechanism underlying cell stress and death in the retina may help develop therapeutic intervention for visual impairment.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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BackgroundReceptor-interacting protein 3 (RIP3), a member of RIP family proteins, has been shown to participate in programmed necrosis or necroptosis in cell biology studies. Evidence suggests that necroptosis may be a mode of neuronal death in the retina.ResultsIn the present study we determined the expression of RIP3 in normal rat retina and its changes following acute high intraocular pressure (aHIOP). RIP3 immunoreactivity (IR) was largely present in the inner retinal layers, localized to subsets of cells expressing neuron-specific nuclear antigen (NeuN), parvalbumin and calbindin in the ganglion cell layer (GCL) and inner nuclear layer (INL). No double labeling was detected for RIP3 with PKC-α or rhodopsin. RIP3 immunoreactivity was increased in the GCL at 6 hr and 12 hr, but reduced at 24 hr in the retina, without apparent alteration in laminar or cellular distribution pattern. Western blot analysis confirmed the above time-dependent alteration in RIP3 protein expression. RIP3 expressing cells frequently co-localized with propidium iodide (PI). A few co-localized cells were observed between RIP3 and Bax or cleaved caspase-3 in the GCL in 12 hr following aHIOP.ConclusionsThe results indicate that RIP3 is expressed differentially in retinal neurons in adult rats, including subsets of ganglion cells, amacrine and horizontal cells. RIP3 protein levels are elevated rapidly following aHIOP. RIP3 labeling co-localized with PI, Bax or cleaved caspase-3 among cells in the ganglion cell layer following aHIOP, which suggest its involvement of RIP3 in neuronal responses to acute ischemic insults.

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Retina-specific activation of a sustained hypoxia-like response leads to severe retinal degeneration and loss of vision

Cited by 20 publications

References 47 publications

Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development

Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development

HIF1A Is Essential for the Development of the Intermediate Plexus of the Retinal Vasculature

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

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