Biomarkers for Diabetic Retinopathy – Could Endothelin 2 Be Part of the Answer?

Binz, N.; Rakoczy, Elizabeth; Rahman, Ireni S. Ali; Vagaja, Nina; Lai, Chooi-May

doi:10.1371/journal.pone.0160442

Cited by 11 publications

(5 citation statements)

References 48 publications

(52 reference statements)

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“…Many studies have implicated Müller cells in neuroprotective pathways for photoreceptor survival (Bringmann et al, 2009;Goh et al, 2016). In particular, EDN2 is produced by photoreceptors in a wide variety of retinal injuries and early stage diseases, and it has been proposed as an early biomarker for diabetic retinopathy (Binz et al, 2016;Bramall et al, 2013;Braunger et al, 2013). When we checked for the presence of this molecule in Faim −/− retinas, we found that both EDN2 immunoreactivity and mRNA expression were increased at 2 months, implying that photoreceptors may have already been impaired by harmful stimuli.…”

Section: Discussionmentioning

confidence: 99%

Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

Sirés

Turch-Anguera

Bogdanov

et al. 2021

J of Neuroscience Research

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Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim −/− ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR.Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim −/− mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation.These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.

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Section: Discussionmentioning

confidence: 99%

Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

Sirés

Turch-Anguera

Bogdanov

et al. 2021

J of Neuroscience Research

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“…Edn2 transcripts are known to be highly expressed during retinopathy of prematurity and diabetic retinopathy. [39][40][41] The induction of Edn2 transcripts has been reported in photoreceptors of diverse photoreceptor degeneration models. 42 In addition, in the acute light damage model, expression of endothelin receptor B (Ednrb) transcripts is increased in Müller glia.…”

Section: Discussionmentioning

confidence: 99%

Cd9 Protects Photoreceptors from Injury and Potentiates Edn2 Expression

Iwagawa

Aihara

Umutoni

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Iwagawa T, Aihara Y, Umutoni D, et al. Cd9 protects photoreceptors from injury and potentiates Edn2 expression. Invest Ophthalmol Vis Sci. 2020;61(3):7. https://doi.org/10.1167/iovs.61.3.7 PURPOSE.Cd9 is a tetraspanin membrane protein that plays various roles in tissue development and disease pathogenesis, especially in cancer, but the expression patterns and function of Cd9 in retinal development and disease are not well understood. We asked its roles during retinal photoreceptor degeneration by using CD9-knockout mice. METHODS.Cd9 knockout mice and rd1 mice were used to examine roles of Cd9 for progression of photoreceptor degeneration. Reverse transcription-polymerase chain reaction and immunohistochemistry were mainly used as analytical methods. RESULTS.Cd9 transcripts were only weakly expressed in retina at embryonic day 14, but its expression level subsequently increased and peaked at around postnatal day 12. In 6week-old female mice derived retina, mRNA expression decreased slightly but was maintained at a significant level. Published RNA-sequencing data and immunohistochemistry indicated that Cd9 was expressed abundantly in Müller glia and weakly in other retinal neurons. Notably, when photoreceptors were damaged, Cd9 expression was increased in rod photoreceptors and decreased in Müller glia. Cd9 knockout mice retinas developed normally; however, once the retina suffered damage, degeneration of photoreceptors was more severe in Cd9 knockout retinas than control retinas. Induction of Edn2, which is known to protect against photoreceptor damage, was severely hampered. In addition, induction of Socs3, which is downstream of gp130 (Il6st), was weaker in Cd9 knockout retinas. CONCLUSIONS.Taken together, these findings indicate that, although Cd9 was dispensable for normal gross morphological development, it protected rod photoreceptors and enhanced Edn2 expression, possibly through modulation of gp130 signaling.

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“…Interestingly, crystallin B2, a family of crystallins that are known to have a role in the adaptive mechanisms taking place in the diabetic retina [ 78 ], is increased twofold in Ins2 Akita mice that received ASC-CM. Endothelin-2, a candidate biomarker for controlled vascular modulation [ 79 , 80 ], was significantly increased in Ins2 Akita mice that received saline with a twofold further increase in mice that received ASCs and ASC-CM. However, for any given gene, the relative differences in expression between Ins2 Akita mice that received ASCs versus ASC-CM was more profound at 3 weeks than at 3 days.…”

Section: Discussionmentioning

confidence: 99%

Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse

et al. 2018

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BackgroundEarly-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model.MethodsIns2Akita mice at 24 weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 μL) or 20× conditioned media from cytokine-primed ASCs (ASC-CM, 1 μL). Age-matched wildtype mice that received saline served as controls. Visual function experiments and histological analyses were performed 3 weeks post intravitreal injection. Biochemical and molecular analyses assessed the ASC-CM composition and its biological effects.ResultsThree weeks post-injection, Ins2Akita mice that received ASCs had ameliorated decreased b-wave amplitudes and vascular leakage but failed to improve visual acuity, whereas Ins2Akita mice that received ASC-CM demonstrated amelioration of all aforementioned visual deficits. The ASC-CM group demonstrated partial amelioration of retinal GFAP immunoreactivity and DR-related gene expression but the ASC group did not. While Ins2Akita mice that received ASCs exhibited occasional (1 in 8) hemorrhagic retinas, mice that received ASC-CM had no adverse complications. In vitro, ASC-CM protected against TNFα-induced retinal endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrated several anti-inflammatory proteins including TSG-6 being highly expressed in cytokine-primed ASC-CM.ConclusionsASCs or their secreted factors mitigate retinal complications of diabetes in the Ins2Akita model. Further investigation is warranted to determine whether ASCs or their secreted factors are safe and effective therapeutic modalities long-term as current locally delivered therapies fail to effectively mitigate the progression of early-stage DR. Nonetheless, our study sheds new light on the therapeutic mechanisms of adult stem cells, with implications for assessing relative risks/benefits of experimental regenerative therapies for vision loss.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1059-y) contains supplementary material, which is available to authorized users.

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Biomarkers for Diabetic Retinopathy – Could Endothelin 2 Be Part of the Answer?

Cited by 11 publications

References 48 publications

Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina

Cd9 Protects Photoreceptors from Injury and Potentiates Edn2 Expression

Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse

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