Diabetic Retinopathy: Mechanism, Diagnosis, Prevention ...€¦ · Editorial Diabetic Retinopathy: Mechanism, Diagnosis, Prevention, and Treatment MohamedAl-Shabrawey,1 WenboZhang,2

Diabetic Retinopathy: Mechanism, Diagnosis, Prevention, andTreatment

Al-Shabrawey, M., Zhang, W., & McDonald, D. (2015). Diabetic Retinopathy: Mechanism, Diagnosis, Prevention,and Treatment. BioMed Research International, 2015, [854593]. https://doi.org/10.1155/2015/854593

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EditorialDiabetic Retinopathy: Mechanism, Diagnosis,Prevention, and Treatment

Mohamed Al-Shabrawey,1 Wenbo Zhang,2 and Denise McDonald3

1Oral Biology and Anatomy, Ophthalmology and Culver Vision Discovery Institute,College of Dental Medicine and Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA2Department of Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA3Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Institute ofClinical Sciences, Block A, Grosvenor Road, Belfast BT12 6BA, UK

Correspondence should be addressed to Mohamed Al-Shabrawey; [email protected]

Received 28 December 2014; Accepted 28 December 2014

Copyright © 2015 Mohamed Al-Shabrawey et al.This is an open access article distributed under theCreativeCommonsAttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.

Diabetic retinopathy (DR) is the most common compli-cation of diabetes and remains a major cause of pre-ventable blindness. Anatomical and functional changes occurin various retinal cells including retinal endothelial cells,neurons, and retinal pigment epithelium prior to clinicalsymptoms of the disease. Early changes include appearance ofmicroaneurysms, leukocyte adhesion, apoptosis of vascular(endothelial cells and pericytes), and neuronal cells. Thechanges progress to involve breakdown of the inner andouter blood retinal barriers causing diabetic macular edema,the most leading cause of vision loss in DR. Capillarydegeneration and development of acellular capillaries leadto impairment of retinal perfusion and subsequent hypoxiaand retinal neovascularization, the hallmark of proliferativediabetic retinopathy (PDR). There are several therapeuticstrategies to manage the DR including laser photocoagu-lation, anti-VEGF, and triamcinolone intraocular injection.These therapeutic interventions are still limited by significantside effects. Therefore, there is still an urgent need to findout new therapies to limit the diminution or loss of visionin diabetic patients. The current special issue through anumber of investigators and experts in the field of DRpresents both research and review articles that highlight novelpathways implicated in the development ofDRand review thepathophysiology and management of DR.

Novel Mechanisms of Diabetic Retinopathy. Effective thera-peutic approaches to restore sight in diabetic patients with

clinically identifiable retinopathy are still lacking and in thisissue S. Z. Safi et al. provide a timely review of currentthinking in field. Firstly, using several scientific databases(PubMed, Ovid MEDLINE, SPORTDiscus, and EMBASEdatabases) they have reviewed the literature focusing onthe molecular mechanisms involved in the pathogenesis ofDR and, secondly on emerging strategies under consider-ation for development of future pharmacological interven-tions. Initially, they described the major pathways widelyrecognized to be involved in disease, namely, the polyolpathway, activation of protein kinase C (KPC) isoforms,increased hexosamine pathway flux and increased advancedglycation end-product (AGE) formation, and oxidative stressalong with several other mechanisms such as the potentialrole of the renin-angiotensin system which are less wellresearched. Arising from this discussion they summarizedestablished preventive measures including general, primary,and secondary preventive strategies before covering noveland emerging therapeutic targets such as PKC inhibitors,VEGF inhibitors, and ACE inhibitors and drugs such asantioxidants. Finally, the authors draw on current evidenceand clinical studies arguing for the use of fenofibrate inhalting disease progression. This review, therefore, providesbackground and context for the research articles included inthis special issue.

Reactive oxygen species (ROS) generated from mito-chondria, NADPH oxidase, and other oxidases are known

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 854593, 2 pageshttp://dx.doi.org/10.1155/2015/854593

http://dx.doi.org/10.1155/2015/854593

2 BioMed Research International

to play an essential role in the pathogenesis of DR ROSmodify redox sensitive kinases and transcription factors suchas NF-𝜅B, Signal Transducers andActivators of Transcriptionproteins (STAT), and activator protein 1 (AP-1) and thereforeinduce inflammatory gene expression in DR. Alternatively,lipid peroxidation and DNA damage induced by ROS causecell death in DR. In this issue, R. Liu et al. discoveredan alternative mechanism on how ROS may play a role inDR. Using human endothelial cells (ECs), they found thatROS treatment induces EC senescence. With gain-and-lossfunction approaches, they provided the first evidence thatROS-induced EC senescence is at least partially mediatedby downregulation of Sirtuin 6 (Sirt6), H3K9, and H3K56deacetylase recently recognized as a novel antiaging andanti-inflammatory molecule. Further, they found that Sirt6antagonizes ROS-induced activation of senescence pathways,such as p21 overexpression and activation of retinoblastoma(Rb) protein. As accelerated aging is currently recognized asone of the key mechanisms of many cardiovascular diseasesincluding DR, this study may lead to a hot area to exploreSirtuins as well as other antiagingmolecules in DR. Certainly,the role of Sirt6 in diabetic animals and patients remainsto be further elucidated. Increased H3K9 acetylation hasbeen found in DR as well as other inflammatory conditions,suggesting that loss of Sirt6 protein and/or function is verylikely involved in DR. A challenge to directly address therole of Sirt6 in DR is the lack of transgenic animals. GlobalSirt6 knockoutmice die within 1month and EC-specific Sirt6knockout mice will be important to test whether lack of Sirt6will accelerate diabetes-induced retinal vascular alterationssuch as permeability and capillary degeneration if these miceare viable.

There is now much evidence to indicate the involvementof a dysregulated inflammatory response in early disease anddefining this role further is likely to offer exciting new avenuesfor therapeutic intervention. To this end, S. Fulzele et al.have focused on characterizing the regulation of adenosinedeaminase 2 (ADA2) by miR-146-3p. They show that thepredicted miR-146-3p target site in the UTR of ADA2 isindeed functional. In addition, since the expression of thismicroRNA is inversely related to ADA2 levels in samplesfrom diabetic patients and similarly treated in vitro modesthe authors conclude that miR-146-3p has a regulatory role indiabetes related inflammation.

Most of the research on the pathogenesis of DR hasprimarily focused on the injury of the neuroretina andthe dysfunction of the inner blood retinal barrier (BRB).Contrary, the impact of diabetes on the function of retinapigment epithelium (RPE) has received less attention andalso the underlying mechanism for RPE dysfunction duringdiabetes remains unclear. The paper by S. Beasley et al.demonstrated for the first time the important role of caspase-14 in the development of diabeticmacular edema (DME).Theexpression of caspase-14 in cultured retinal pigment epithelialcells (ARPE-19) is correlated with the disruption of RPE bar-rier function and hyperpermeability. In addition, knockingdown the caspase-14 in RPE abrogated the hyperglycemia-induced RPE hyperpermeability. Interestingly, this paper alsodemonstrated that caspase-14 might play a role upstream

from other caspases to mediate inflammatory and apoptoticresponses. In conclusion, this paper suggests caspase-14 as anovel player as well as therapeutic target in DR.

Biomarkers of Diabetic Retinopathy. Diabetic retinopathy is aprogressive disease, which is clinically identifiable only at anadvanced stage; therefore markers that indicate early diseasestatus would be of major benefit in managing disease pro-gression. Since there are early subclinical changes occurringin retina prior to clinical symptoms, it is necessary to findout specific early biomarkers that predict the pattern andprogress of these changes to an advanced stage of DR. Thediscovery of biomarkers to aid in the identification of patientsmost likely to develop severe DME and PDR is essential forbetter treatment of this disease. In support of this concept,B. A. Mysona et al. presented here an interesting clinicalstudy in which they tested whether changes in proNGF/NGFlevels observed in vitreous will be matched in serum andthus provide rationale to examine proNGF as a biomarkerfor DR. This study included analysis of serum and vitreoussamples from nondiabetic patients and patients with PDR.Interestingly, the proNGF/NGF imbalance in serum wascomparable to the imbalance of proNGF/NGF in vitreous ofpatients with PDR suggesting that serum proNGF/NGF ratiomight act as a novel biomarker that reflects the progress ofDR.

Increasing evidence indicates that inflammation is a keyplayer in DR. Increases in vitreous inflammatory cytokinessuch as IL-6, VEGF, MCP-1, and IP-10 have been foundto be positively associated with the progression of DR andthe severity of macular edema. However, it is difficult toget vitreous samples and therefore the feasibility of usingvitreous cytokines as biomarker is very low. In this issue,N. Dong et al. analyzed an array of inflammatory cytokinesin the aqueous humor in relation to macular edema indiabetic patients following uncomplicated phacoemulsifica-tion cataract surgery. They found that concentrations ofinflammatory cytokines such as IL-1𝛽, IL-6, IL-8, MCP-1, IP-10, and VEGF are positively associated with macularedema whereas levels of anti-inflammatory cytokines suchas IL-10 and IL-12 are negatively associated with macularedema. Given that it is easy to obtain the aqueous humor,this study highlights the possibility to use these cytokinesas biomarkers for diabetic macular edema. Certainly, it ismuch easier to obtain tears than aqueous humor; it would beinteresting to further explore whether there is an associationof tear inflammatory cytokines with diabetic macular edemaand neovascularization. This study also brings an interestingquestion about where these inflammatory cytokines aregenerated. Are they diffusing into aqueous humor or arethey generated from cells in ciliary body or cornea? Furtherexploration of their source will help to better understand thedevelopment of DR.

Mohamed Al-ShabraweyWenbo Zhang

Denise McDonald

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Diabetic Retinopathy: Mechanism, Diagnosis, Prevention ...€¦ · Editorial Diabetic Retinopathy: Mechanism, Diagnosis, Prevention, and Treatment MohamedAl-Shabrawey,1 WenboZhang,2