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Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2019) | Viewed by 59504

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Prof. Dr. Peter Koulen

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Departments of Ophthalmology and Basic Medical Science, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
Interests: drug target discovery and drug development for disorders of the CNS and retina; calcium signaling; neuroprotection; neurodegeneration; synaptic signaling; neurophysiology
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Dear Colleagues,

The identification of mechanisms underlying the pathophysiology and therapies of diabetic retinopathy continues to be an area of significant research efforts, attracting scientists from a diverse range of fields, including neuroscience, pharmacology, and medicinal chemistry among several others. With the ultimate goal to generate intervention strategies that slow or even reverse structural and functional degeneration of the retina and that attenuate or eliminate vascular complications input from numerous fields, such as neurology, ophthalmology, and endocrinology appears critically needed as effective therapies for diabetic retinopathy are lacking.

Research efforts towards treating or curing diabetic retinopathy are characteristic for how clinical practice, basic and translational research inform each other and how such interactions can result in novel therapeutic strategies of high clinical relevance. Recent methodological advances in synthetic and medicinal chemistry, mass spectrometry, proteomics, drug target discovery and drug development have generated significant developments in this field. Therefore, this Special Issue invites manuscript submissions, namely research and review papers, targeting the gamut of methodological and scientific innovation in this field. Of specific interest to this special issue are papers focused on the discovery and mechanistic characterization of novel drug targets, signaling pathways, and mechanisms of action as they are relevant for diabetic retinopathy. These contributions can be general and broad in their basic science and translational research focus or highly focused on specific research models related to structural and functional degeneration of the retina and vascular complications.

Round 1 deadline: 17 October 2018.

Dr. Peter Koulen
Guest Editor

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Keywords

Neuroprotection
retina
diabetic macular edema
proliferative and non-proliferative diabetic retinopathy
therapy development
pathophysiology

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Published Papers (8 papers)

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Research

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10 pages, 4093 KiB

Open AccessArticle

Loss of Response Gene to Complement 32 (RGC-32) in Diabetic Mouse Retina Is Involved in Retinopathy Development

by Wen-Ling Liao, Jane-Ming Lin, Shih-Ping Liu, Shih-Yin Chen, Hui-Ju Lin, Yeh-Han Wang, Yu-Jie Lei, Yu-Chuen Huang and Fuu-Jen Tsai

Int. J. Mol. Sci. 2018, 19(11), 3629; https://doi.org/10.3390/ijms19113629 - 17 Nov 2018

Cited by 11 | Viewed by 3380

Abstract

Diabetic retinopathy (DR) is a severe and recurrent microvascular complication in diabetes. The multifunctional response gene to complement 32 (RGC-32) is involved in the regulation of cell cycle, proliferation, and apoptosis. To investigate the role of RGC-32 in the development of DR, we used human retinal microvascular endothelial cells under high-glucose conditions and type 2 diabetes (T2D) mice (+Lepr^db/ + Lepr^db, db/db). The results showed that RGC-32 expression increased moderately in human retinal endothelial cells under hyperglycemic conditions. Histopathology and RGC-32 expression showed no significant changes between T2D and control mice retina at 16 and 24 weeks of age. However, RGC-32 expression was significantly decreased in T2D mouse retina compared to the control group at 32 weeks of age, which develop features of the early clinical stages of DR, namely reduced retinal thickness and increased ganglion cell death. Moreover, immunohistochemistry showed that RGC-32 was predominantly expressed in the photoreceptor inner segments of control mice, while the expression was dramatically lowered in the T2D retinas. Furthermore, we found that the level of anti-apoptotic protein Bcl-2 was decreased (approximately 2-fold) with a concomitant increase in cleaved caspase-3 (approximately 3-fold) in T2D retina compared to control. In summary, RGC-32 may lose its expression in T2D retina with features of DR, suggesting that it plays a critical role in DR pathogenesis. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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15 pages, 3484 KiB

Open AccessArticle

Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes

by Patricia Bogdanov, Olga Simó-Servat, Joel Sampedro, Cristina Solà-Adell, Marta Garcia-Ramírez, Hugo Ramos, Marta Guerrero, Josep Maria Suñé-Negre, Josep Ramon Ticó, Bruno Montoro, Vicente Durán, Luís Arias, Cristina Hernández and Rafael Simó

Int. J. Mol. Sci. 2018, 19(11), 3578; https://doi.org/10.3390/ijms19113578 - 13 Nov 2018

Cited by 21 | Viewed by 4700

Abstract

Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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15 pages, 4259 KiB

Open AccessArticle

Effects of Liposomal Formulation of Citicoline in Experimental Diabetes-Induced Retinal Neurodegeneration

by Patricia Bogdanov, Joel Sampedro, Cristina Solà-Adell, Olga Simó-Servat, Carla Russo, Luisa Varela-Sende, Rafael Simó and Cristina Hernández

Int. J. Mol. Sci. 2018, 19(8), 2458; https://doi.org/10.3390/ijms19082458 - 20 Aug 2018

Cited by 28 | Viewed by 6836

Abstract

Diabetic retinopathy (DR) has been classically considered a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is also an early event in the pathogenesis of DR. Citicoline has been successfully used as a neuroprotective agent in the treatment of glaucoma but their effects on DR remain to be elucidated. On this basis, the main aim of the present study was to evaluate the effect of topical administration of citicoline in liposomal formulation on retinal neurodegeneration in db/db mouse and to investigate the underlying mechanisms of action. The treatment (citicoline or vehicle) was topically administered twice daily for 15 days. Retinal analyses were performed in vivo by electroretinography and ex vivo by using Western blot and immunofluorescence measurements. We found that the liposomal formulation of citicoline prevented glial activation and neural apoptosis in the diabetic retina. The main mechanism implicated in these beneficial effects were the inhibition of the downregulation of synaptophysin and its anti-inflammatory properties by means of preventing the upregulation of NF-κB and TNF-α (Tumor Necrosis Factor α) induced by diabetes. Overall, these results suggest that topical administration of citicoline in liposomal formulation could be considered as a new strategy for treating the early stages of DR. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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15 pages, 9442 KiB

Open AccessArticle

Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1

by Esraa Shosha, Zhimin Xu, S. Priya Narayanan, Tahira Lemtalsi, Abdelrahman Y. Fouda, Modesto Rojas, Ji Xing, David Fulton, R. William Caldwell and Ruth B. Caldwell

Int. J. Mol. Sci. 2018, 19(4), 1215; https://doi.org/10.3390/ijms19041215 - 17 Apr 2018

Cited by 56 | Viewed by 7059

Abstract

We have recently found that diabetes-induced premature senescence of retinal endothelial cells is accompanied by NOX2-NADPH oxidase-induced increases in the ureohydrolase enzyme arginase 1 (A1). Here, we used genetic strategies to determine the specific involvement of A1 in diabetes-induced endothelial cell senescence. We used A1 knockout mice and wild type mice that were rendered diabetic with streptozotocin and retinal endothelial cells (ECs) exposed to high glucose or transduced with adenovirus to overexpress A1 for these experiments. ABH [2(S)-Amino-6-boronohexanoic acid] was used to inhibit arginase activity. We used Western blotting, immunolabeling, quantitative PCR, and senescence associated β-galactosidase (SA β-Gal) activity to evaluate senescence. Analyses of retinal tissue extracts from diabetic mice showed significant increases in mRNA expression of the senescence-related proteins p16^INK4a, p21, and p53 when compared with non-diabetic mice. SA β-Gal activity and p16^INK4a immunoreactivity were also increased in retinal vessels from diabetic mice. A1 gene deletion or pharmacological inhibition protected against the induction of premature senescence. A1 overexpression or high glucose treatment increased SA β-Gal activity in cultured ECs. These results demonstrate that A1 is critically involved in diabetes-induced senescence of retinal ECs. Inhibition of arginase activity may therefore be an effective therapeutic strategy to alleviate diabetic retinopathy by preventing premature senescence. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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1738 KiB

Open AccessArticle

Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin

by Saori Deguchi, Hiroko Otake, Yosuke Nakazawa, Noriko Hiramatsu, Naoki Yamamoto and Noriaki Nagai

Int. J. Mol. Sci. 2017, 18(12), 2720; https://doi.org/10.3390/ijms18122720 - 15 Dec 2017

Cited by 19 | Viewed by 3990

Abstract

Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. However, the current instillation systems do not allow a sufficient amount of drug required to treat retinopathy to reach the posterior segment (retina); therefore, a new formulation targeting the posterior segment is expected as therapy for retinopathy. We prepared ophthalmic formulations containing nilvadipine nanoparticles (NIL_nano), and demonstrated whether the instillation of NIL_nano can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats) in this study. NIL_nano (mean particle size, 77 nm) was prepared by wet bead mill treatment, with the inclusion of various additives (2-hydroxypropyl-β-cyclodextrin, benzalkonium chloride, d-mannitol, and methylcellulose). Retinal dysfunction was observable two weeks after rats received intraperitoneal injections of streptozotocin (100 mg/kg × 2, consecutive days, STZ rat). Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The retinal thickness, measured as the distance between the ganglion cell layer and the distal border of the outer nuclear layer, increased two weeks after the injection of streptozotocin, resulting in decreases in the levels of a-waves, b-waves, and oscillatory potential amplitudes in ERG of rats. The instillation of NIL_nano allowed the topical supplement of nilvadipine into the retina, and repeated instillation of NIL_nano (2 times/day) attenuated the retinal disorders led by the excessive streptozotocin. In conclusion, we found that retinal dysfunction in rats injected with streptozotocin can be prevented by the NIL_nano instillation. These results are useful in further studies aimed at the therapeutic treatment of retinopathy. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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Review

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25 pages, 1911 KiB

Open AccessReview

Lymphatic Vascular Structures: A New Aspect in Proliferative Diabetic Retinopathy

by Erika Gucciardo, Sirpa Loukovaara, Petri Salven and Kaisa Lehti

Int. J. Mol. Sci. 2018, 19(12), 4034; https://doi.org/10.3390/ijms19124034 - 13 Dec 2018

Cited by 20 | Viewed by 6031

Abstract

Diabetic retinopathy (DR) is the most common diabetic microvascular complication and major cause of blindness in working-age adults. According to the level of microvascular degeneration and ischemic damage, DR is classified into non-proliferative DR (NPDR), and end-stage, proliferative DR (PDR). Despite advances in the disease etiology and pathogenesis, molecular understanding of end-stage PDR, characterized by ischemia- and inflammation-associated neovascularization and fibrosis, remains incomplete due to the limited availability of ideal clinical samples and experimental research models. Since a great portion of patients do not benefit from current treatments, improved therapies are essential. DR is known to be a complex and multifactorial disease featuring the interplay of microvascular, neurodegenerative, metabolic, genetic/epigenetic, immunological, and inflammation-related factors. Particularly, deeper knowledge on the mechanisms and pathophysiology of most advanced PDR is critical. Lymphatic-like vessel formation coupled with abnormal endothelial differentiation and progenitor cell involvement in the neovascularization associated with PDR are novel recent findings which hold potential for improved DR treatment. Understanding the underlying mechanisms of PDR pathogenesis is therefore crucial. To this goal, multidisciplinary approaches and new ex vivo models have been developed for a more comprehensive molecular, cellular and tissue-level understanding of the disease. This is the first step to gain the needed information on how PDR can be better evaluated, stratified, and treated. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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17 pages, 6103 KiB

Open AccessReview

Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy

by François Willermain, Lisa Scifo, Célia Weber, Laure Caspers, Jason Perret and Christine Delporte

Int. J. Mol. Sci. 2018, 19(4), 1056; https://doi.org/10.3390/ijms19041056 - 2 Apr 2018

Cited by 41 | Viewed by 6511

Abstract

Diabetic retinopathy is a frequent eyesight threatening complication of type 1 and type 2 diabetes. Under physiological conditions, the inner and the outer blood-retinal barriers protect the retina by regulating ion, protein, and water flux into and out of the retina. During diabetic retinopathy, many factors, including inflammation, contribute to the rupture of the inner and/or the outer blood-retinal barrier. This rupture leads the development of macular edema, a foremost cause of sight loss among diabetic patients. Under these conditions, it has been speculated that retinal pigmented epithelial cells, that constitute the outer blood-retinal barrier, may be subjected to hyperosmolar stress resulting from different mechanisms. Herein, we review the possible origins and consequences of hyperosmolar stress on retinal pigmented epithelial cells during diabetic retinopathy, with a special focus on the intimate interplay between inflammation and hyperosmolar stress, as well as the current and forthcoming new pharmacotherapies for the treatment of such condition. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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31 pages, 1541 KiB

Open AccessReview

Role of Inflammation in Diabetic Retinopathy

by Anne Rübsam, Sonia Parikh and Patrice E. Fort

Int. J. Mol. Sci. 2018, 19(4), 942; https://doi.org/10.3390/ijms19040942 - 22 Mar 2018

Cited by 541 | Viewed by 19900

Abstract

Diabetic retinopathy is a common complication of diabetes and remains the leading cause of blindness among the working-age population. For decades, diabetic retinopathy was considered only a microvascular complication, but the retinal microvasculature is intimately associated with and governed by neurons and glia, which are affected even prior to clinically detectable vascular lesions. While progress has been made to improve the vascular alterations, there is still no treatment to counteract the early neuro-glial perturbations in diabetic retinopathy. Diabetes is a complex metabolic disorder, characterized by chronic hyperglycemia along with dyslipidemia, hypoinsulinemia and hypertension. Increasing evidence points to inflammation as one key player in diabetes-associated retinal perturbations, however, the exact underlying molecular mechanisms are not yet fully understood. Interlinked molecular pathways, such as oxidative stress, formation of advanced glycation end-products and increased expression of vascular endothelial growth factor have received a lot of attention as they all contribute to the inflammatory response. In the current review, we focus on the involvement of inflammation in the pathophysiology of diabetic retinopathy with special emphasis on the functional relationships between glial cells and neurons. Finally, we summarize recent advances using novel targets to inhibit inflammation in diabetic retinopathy. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms underlying Pathophysiology and Therapies)

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