Aqueous Humor Biomarkers of Müller Cell Activation in Diabetic Eyes

Vujosevic, Stela; Micera, Alessandra; Bini, Silvia; Berton, Marianna; Esposito, Graziana; Midena, Edoardo

doi:10.1167/iovs.15-16554

Cited by 78 publications

(73 citation statements)

References 29 publications

(46 reference statements)

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“…Activation of Müller cells, shown by an increased expression of GFAP, is a sign of human early DR pathology [42]. Müller cells are also a major source of retinal VEGF in diabetic mice and Müller cell-derived VEGF plays an essential and causative role in retinal inflammation and vascular leakage in DR [21].…”

Section: Discussionmentioning

confidence: 99%

Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

Qiu

Liu²,

Wang

2017

Cell Physiol Biochem

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Background/Aims: Interleukin (IL)-17A, a proinflammatory cytokine, has been implicated in several autoimmune diseases. However, it is unclear whether IL-17A is involved in diabetic retinopathy (DR), one of the most serious complications of autoimmune diabetes. This study aimed to demonstrate that IL-17A exacerbates DR by affecting retinal Müller cell function. Methods: High glucose (HG)-treated rat Müller cell line (rMC-1) was exposed to IL-17A, anti-IL-17A-neutralizing monoclonal antibody (mAb) or/and anti-IL-17 receptor (R)A-neutralizing mAb for 24 h. For in vivo study, DR was induced by intraperitoneal injections of streptozotocin (STZ). DR model mice were treated with anti-IL-17A mAb or anti-IL-17RA mAb in the vitreous cavity. Mice that were prepared for retinal angiography were sacrificed two weeks after intravitreal injection, while the rest were sacrificed two days after intravitreal injection. Results: IL-17A production and IL-17RA expression were increased in both HG-treated rMC-1 and DR retina. HG induced rMC-1 activation and dysfunction, as determined by the increased GFAP, VEGF and glutamate levels as well as the downregulated GS and EAAT1 expression. IL-17A exacerbated the HG-induced rMC-1 functional disorders, whereas either anti-IL-17A mAb or anti-IL-17RA mAb alleviated the HG-induced rMC-1 disorders. Intravitreal injections with anti-IL-17A mAb or anti-IL-17RA mAb in DR model mice reduced Müller cell dysfunction, vascular leukostasis, vascular leakage, tight junction protein downregulation and ganglion cell apoptosis in the retina. Conclusions: IL-17A aggravates DR-like pathology at least partly by impairing retinal Müller cell function. Blocking IL-17A is a potential therapeutic strategy for DR.

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Section: Discussionmentioning

confidence: 99%

Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

Qiu

Liu²,

Wang

2017

Cell Physiol Biochem

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“…Moreover, Vujosevic et al [42] detected a significant increase in AH AQP1 in diabetic patients with retinopathy compared both to diabetics without DR (approximately 1.4-fold increase) and healthy subjects (approximately 2-fold increase). Similar to AQP4, the function of AQP1 is also involved in the regulation of the transcellular flow of free water [55] .…”

Section: Retinal Glial Cell Activationmentioning

confidence: 95%

“…Müller cells regulate the flow of potassium released by active neurons, which if present in excess in the extracellular space may induce neuronal excitability. Recently, Vujosevic et al [42] detected that AQP4 was significantly increased in AH of diabetic patients, even in those without clinical signs of retinopathy, versus healthy subjects. In diabetic patients with retinopathy, AQP4 was approximately 25-fold increased versus healthy subjects.…”

Section: Retinal Glial Cell Activationmentioning

confidence: 99%

“…The increase in GFAP concentration is considered a common marker for reactive gliosis and an early sensor for retinal stress [32,44] . Vujosevic et al [42] detected that at early stages of DM, in diabetics without DR, there is no significant change in GFAP versus controls, whereas in diabetics with DR, there is a significant increase in GFAP. The increase of GFAP in AH may be the consequence of macroglial cell activation, namely Müller cells activation [45][46][47][48][49] .…”

Section: Retinal Glial Cell Activationmentioning

confidence: 99%

“…Recently, Vujosevic et al [42] measured these specific biomarkers in the aqueous humor (AH) of diabetic patients compared to controls.…”

Section: Retinal Glial Cell Activationmentioning

confidence: 99%

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Emerging Insights into Pathogenesis

Midena

Pilotto

2017

Management of Diabetic Retinopathy

Self Cite

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Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus (DM). Persistent hyperglycemia leads to the activation of multiple cellular pathways involved in the pathogenesis of DR, resulting in increased inflammation, oxidative stress, and vascular dysfunction. DR has been considered a "chronic, low-grade inflammatory disease of the retina". However, an increasing body of evidence suggests that inflammation and neurodegeneration both occur in human diabetes even before the development of clinical signs of DR. One of the first signs of inflammation in DM is the activation of retinal glia cells (RGC). RGC include microglia and macroglial cells (Müller cells and astrocytes). Activated RGC release cytotoxic substances responsible for the recruitment of leukocytes, blood-retinal barrier breakdown, direct glial dysfunction, and neuronal cell death. Recently, many inflammatory mediators, growth factors, and other molecules have been investigated in human vitreous and aqueous humor samples to better understand, in vivo, the multiple pathways and mechanisms leading to the pathogenesis of DR and its complications, such as diabetic macular edema, with potential for more tailored treatment. Moreover, non-invasive techniques, like optical coherence tomography, have allowed to detect new findings in the retinal layers, such as the hyperreflective intraretinal spots, which have been hypothesized to represent an in vivo marker of microglial activation, and early neural cell loss, confirming the hypothesis that neurodegeneration occurs early both in type 1 and 2 diabetes. These new emerging insights foster a better understanding of the pathogenesis of DR, which can no longer be considered as a pure retinal vascular complication of DM.

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Where Microneedle Meets Biomarkers: Futuristic Application for Diagnosing and Monitoring Localized External Organ Diseases

Himawan

Vora

Permana

et al. 2022

Adv Healthcare Materials

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Extracellular tissue fluids are interesting biomatrices that have recently attracted scientists' interest. Many significant biomarkers for localized external organ diseases have been isolated from this biofluid. In the diagnostic and disease monitoring context, measuring biochemical entities from the fluids surrounding the diseased tissues may give more important clinical value than measuring them at a systemic level. Despite all these facts, pushing tissue fluid-based diagnosis and monitoring forward to clinical settings faces one major problem: its accessibility. Most extracellular tissue fluid, such as interstitial fluid (ISF), is abundant but hard to collect, and the currently available technologies are invasive and expensive. This is where novel microneedle technology can help tackle this significant obstacle. The ability of microneedle technology to minimally invasively access tissue fluid-containing biomarkers will enable ISF and other tissue fluid utilization in the clinical diagnosis and monitoring of localized diseases. This review attempts to present the current pursuit of the application of microneedle systems as a diagnostic and monitoring platform, along with the recent progress of biomarker detection in diagnosing and monitoring localized external organ diseases. Then, the potential use of various microneedles in future clinical diagnostics and monitoring of localized diseases is discussed by presenting the currently studied cases.

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Aqueous Humor Biomarkers of Müller Cell Activation in Diabetic Eyes

Abstract: Glial fibrillary acidic protein, AQP1, and AQP4-biomarkers of Müller cell activity-are significantly increased in human eyes with diabetes, confirming that Müller cells are precociously affected by diabetes mellitus.

Cited by 78 publications

References 29 publications

Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

Emerging Insights into Pathogenesis

Where Microneedle Meets Biomarkers: Futuristic Application for Diagnosing and Monitoring Localized External Organ Diseases

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