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12 June 2023: Review Articles  

Frontiers in Understanding the Pathological Mechanism of Diabetic Retinopathy

Lei Zhan1ABDEF*

DOI: 10.12659/MSM.939658

Med Sci Monit 2023; 29:e939658

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Abstract

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ABSTRACT: The retina is a light-sensitive membrane responsible for optical signal reception and concatenation with the optic nerve. Retinal damage causes blurred vision or visual dysfunction. Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) that is induced by the interaction of multiple factors and mechanisms. Hyperglycemia and hypertension are potential risk factors for DR. With the growing number of DM patients, the incidence of DR increases if DM is untreated. Epidemiological data show that DR is a leading cause of blindness in working-aged adults. Regular ophthalmological check-ups, laser treatment, and interdisciplinary consultation for reducing visual atrophy can help prevent and treat DR. Although the pathogenesis of DR is complex, and the exact pathological mechanism of DR needs to be further elucidated to promote new drug research and development against DR. The entire pathological process of DR involves increased oxidative stress (microvascular dysfunction, mitochondrial dysfunction) and chronic inflammation (inflammatory infiltration, cell necrosis) and impairment of the renin-angiotensin system (microcirculation dysregulation). This review aims to summarize the pathological mechanisms underlying the development of DR to improve clinical diagnosis and effective treatment of DR.

Keywords: Diabetic Retinopathy, Blindness, Pathogen-Induced Protease, P69, Pathology, Molecular, Adult, Humans, Middle Aged, Retinal Diseases, Inflammation, Retina, Atrophy, Diabetes Mellitus

Background

DR is an ophthalmic disease clinically characterized by persistent retinal lesions caused by glucose metabolism dysfunction. As a severe symptom in DM, DR presents with blurred vision, decreased vision, and blindness [1]. Globally, the incidence and progression of DR have worsened in recent decades, and early diagnosis and effective treatment should be priorities [2]. Although clinical progress has been made in treatment DR, the poor lower fundus inspection rates limit screening of DR. Thus, understanding the pathogenesis of DR is important for expediting earlier treatment of DR to reduce the incidence of vision impairment and blindness [3]. However, the exact pathogenic mechanism of DR is not clearly understood. A growing body of evidence indicates that low-grade inflammation exerts a key role in the pathogenesis and development of DR, involving cytokine infiltration, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1) [4]. The actions of inflammatory cytokines and vascular endothelial growth factor can synergistically damage the blood–retinal barrier, induce vascular damage and neuroinflammation, promote pathological angiogenesis, and cause diabetic macular edema before development of DR [5]. Additionally, retinal cell types in DR, including Müller glia, astrocytes, microglia, retinal pigment epithelial cells, are activated to release inflammatory mediators, gradually inducing cell apoptosis and vascular damage [6]. Promising treatments targeting inflammatory or oxidative molecules or correlative signaling pathways help to suppress retinal injury and prevent DR progression. The present article reviews the existing literature and summarizes the molecular mechanisms involved in the pathogenesis of DR, and proposes inflammation- and oxidative stress-based treatments for DR.

Retinal Physiological Structure

The retinal tissue structure has highly interconnected functions, and can be subdivided into 10 layers from outside to inside: pigment epithelial cell layer, optic cell layer, outer membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, middle limiting membrane, ganglion cell layer, nerve fiber layer, and inner boundary membrane [7]. The physical structure and physiological function in each layer are described briefly as follows. (1) The pigment epithelial cell layer is composed of a single layer of dwarf columnar pigment cells, which maintains the metabolism. (2) The optic cell layer includes cone cells and rod cells. Cone cells can distinguish colors, but are only excited when stimulated by strong light. Rods cells, also known as photoreceptors, can accept light stimuli and convert them into electrical energy to release nerve impulses. (3) The outer membrane is a membrane-like structure formed by the interconnection of the tips of the lateral process of radial glial cells, which has the function of sensing light stimulation. (4) The outer nuclear layer consists of the cell bodies of cone cells and rod cells, which can stabilize the nuclear membrane. (5) The outer plexus layer consists of the endophytes of cone cells and rod cells and the dendrites of bipolar cells. (6) The inner nuclear layer is composed of bipolar cells, horizontal cells, non-spiky cells and radial glial cells. (7) The middle limiting membrane is composed of axons of bipolar cells, dendrites of non-elongated cells, and ganglion cells. (8) The ganglion cell layer is related to conduction function. (9) The nerve fiber layer is made up of axons of ganglion cells that can transmit commands from the brain. (10) The inner boundary membrane is a thin film between the inner surface of the retina and the surface of the vitreous body. The physical structure characteristics of the retina are highlighted in Figure 1.

Retinal tissue has a fine and complex structure, and damage to each layer of the structure can cause visual impairment and other symptoms, including retinal detachment, retinal periphlebitis, and maculopathy [8]. Retinal lesions, hemorrhages, and exudates are the critical pathological symptoms of DR [9]. Non-proliferative DR refers to the earliest condition of DR and is commonly asymptomatic. Clinically, the severity of DR is determined by using a semi-quantitative scoring system on the basis of retinal lesions [10]. Proliferative DR is characterized by retinal neovascularization, and it can lead to irreversible vision loss and impairment over time [11].

Blood–Retinal Barrier

The blood–retinal barrier (BRB) is composed of inner and outer components in which the inner BRB consists of tight junctions within retinal capillary endothelial cells, and the outer BRB is formed of tight junctions within retinal pigment epithelial cells. The BRB is important for maintaining normal visual function and eye tissue in specific locations [12]. The structural integrity of the BRB plays the pivotal role in maintenance of retinal function and microenvironment via modulation of transcellular and paracellular transport actions. Notably, BRB damage can cause formation of edema, a hallmark characteristic of retinal disorders [13]. The typical retinal diseases, such as DR and age-related macular degeneration (AMD), are directly related to abnormal changes of the BRB [14].

Pathological Changes of the BRB in DR

CHANGES OF BRB AND RETINAL HOMEOSTASIS IN DR:

In DR, high blood glucose levels caused by DM can disrupt cell–cell communication and then trigger impairment of retinal homeostasis. Hyperglycemia changes the activity of connexin genes and interrelated intercellular communication in retinal vascular cells [17]. Hyperglycemia causes cell death, damages vascular permeability, and affects retinal homeostasis and interactions between pericytes, endothelial cells, and Müller cells, which characterize the underlying pathogenesis of DR [18]. A previous study using an animal model of DR found reduced retinal blood flow, similar to that observed in the early stages of DM, induced by hyperglycemia, including breakdown of BRB, emergence of microhemorrhages, and development of ischemia [19]. It was reported that endogenous vascular endothelial growth factor (VEGF) can induce retinal leukostasis and breakdown of the BRB, and VEGF164 is a potential proinflammatory marker in early DR [20]. Platelet deposition in the vasculature of people with DR is secondary to endothelial cell death caused by leukocytes, subsequently affecting the BRB. Thus, platelet activation and its activated cytokines may be potential biomarkers of DR [21].

SELECTIVE LOSS OF PERICYTES: Selective pericyte loss is a pathological hallmark of early DR, and loss of pericytes may initiate disruption of the BRB in DM [22]. The structure of the BRB is mainly formed through tightly interconnected capillary endothelial cells covered with pericytes. The platelet-derived growth factor (PDGF) signaling pathway is required for construction of the BRB via targeting recruitment of pericytes to proliferating retinal vessels. Altered pericyte adhesion to retinal vessels, based on BRB impairment, may be responsible for the underlying pathogenesis of DR [23]. Therefore, targeting inhibition of loss of pericytes may be a potential treatment of DR.

RETINAL ENDOTHELIAL CELL DEATH: Recruitment of numerous leukocytes to the DR-related vasculature causes endothelial cell impairment or death and subsequent BRB breakdown [24]. An in vivo study found that leukocyte subsets induce retinal endothelial cell death as a leading cause of BRB damage in early DR, suggesting the role of natural killer T cells in modulating the pathophysiology of DR [25]. When leukostasis occurs, vasodilatation and inflammation can induce early BRB breakdown, eventually leading to retinal endothelial cell damage and death [26].

Molecular Mechanisms in DR

OXIDATIVE STRESS:

Oxidative stress is one of adverse outcomes in metabolic abnormalities mediated by high blood glucose levels, basically comprising activation of the polyol pathway and hexosamine pathway, over-expression of protein kinase C (PKC), and deposition of advanced glycation end-product (AGE). Oxidative stress has been identified as a key contributor to the pathological mechanism of DR [27]. Excessive production of reactive oxygen species (ROS) can lead to mitochondrial impairment, lipid peroxidation, cell apoptosis, inflammatory stress, and retinal dysfunction [28].

PKC PATHWAY:

PKC refers to a family of phospholipid-dependent serine/threonine protein kinases that are mainly expressed in the retina, kidney, and heart tissues. PKC activation is related to cellular events, including proliferation, differentiation, and apoptosis [29]. Other studies have indicated that activation of PKC can exert an important role in the development of DR, as shown in an in vitro DR model [30]. Furthermore, induction of PKC enhances excessive expression of endothelin, a potent vasoconstrictor, causing retinal impairment through impairing endothelial function in blood vessels [31]. High glucose levels can cause activation of PKC isoforms, increase production of AGE, increase levels of glucose, and activate release of ROS [32]. In addition, an in vivo study found increased PKC expression and activation of the PKC signaling pathway in chemical-induced DR [33], suggesting that the PKC pathway is a potential mechanism in development of DR.

POLYOL PATHWAY:

The polyol pathway is involved in glucose metabolism in the activated stage in DM, affecting stabilization between nicotinamide adenine dinucleotide (NADH) and NAD+. Dysregulation of the polyol pathway can cause oxidative injury to DNA and proteins, subsequently causing DM and its associated complications, including DR [34]. Human endothelial cells in retinal vessels participate in the process of aldose reductase. Some promoter region polymorphisms in the aldose reductase gene are involved in susceptibility to and progression of DR [35]. It is reported that superabundant expression of aldose reductase may be a molecular mechanism of human DR through regulating the polyol (sorbitol) pathway for glucose metabolism [36]. Additionally, the specific polymorphisms in polyol pathway genes of ALR2 rs759853 and SDH rs2055858 are found to be associated with different levels of risk of DR [37]. The underlying mechanism by which the polyol pathway is associated with the pathogenesis of DR may involve modulating oxidative stress, inflammatory reactions, and homeostasis [38].

HEXOSAMINE PATHWAY:

The hexosamine pathway is associated with the protein-functional maturation and cellular communications involved in regulating age-related proteotoxicity [39]. The hexosamine biosynthetic pathway mediates nutrient utilization and cellular stress response via glucose metabolism [40]. Interestingly, the potential role of the hexosamine biosynthetic pathway may contribute to the occurrence and development of metabolic diseases, including DM [41]. DR is one of the most severe microvascular complications caused by high blood glucose levels via the main molecular pathways, such as the hexosamine pathway [42]. Furthermore, most stages in DR pathogenesis closely involve excessive ROS release, inflammatory stress, and cell death [43].

INFLAMMATORY STRESS:

Inflammation plays a crucial role in the pathogenesis of DM and in the metabolic symptoms and subsequent development of DM-related complications, such as DR [44]. Microvascular lesions are a DR-associated feature, and chronic inflammation contributes to the molecular pathogenesis of DR [45]. VEGF is highly activated through induction of hyperglycemic changes and hypoxia stress in the tissues. Other proinflammatory molecules are mediated by diversified cytokines, including TNF-α and interleukin-6 (IL-6) and other growth factors inducing vasopermeability and proliferative DR. There is evidence of inflammation and angiogenesis crosstalk in DR [46]. A growing body of evidence suggests that DR is a low-level inflammatory disease caused by hyperglycemia, and its main features are oxidative stress, cell apoptosis, and neovascularization. Toll-like receptors are a functional family of pattern-recognition receptors that contribute to development of inflammatory stress [47]. Thus, anti-inflammatory strategies may be promising treatments for clinical DR.

RENIN-ANGIOTENSIN SYSTEM:

It is clinically observed that hypertension increases the risk of developing DR, and hypertension inhibitors can be used to treat retinopathy. The renin-angiotensin system (RAS) can be activated by prolonged high blood glucose levels, characterized by increased angiotensin II (AII) expression in proliferative DR [48]. Therefore, the use of AII Type 1 (AT1) inhibitors seems to be an effectively therapeutic option to clinically manage DR [49]. Additionally, Ang II, which is a known bioactive ingredient of the RAS, is significantly elevated in DR patients, in which Ang II mediates neurovascular impairment, contributing to the development of DR. These ongoing events reveal that the Ang II pathway in DR may an early mechanism involved in blurred vision in people with DR [50]. Other evidence suggests that actions of AGEs and RAS affect diverse pathological processes in DR, characterized by crosstalk between the AGEs and RAS molecular pathways [51]. Taken together, the above evidence suggests that pharmacologically targeting inhibition of RAS or related pathways may be a promising regimen for clinical treatment of DR [52].

Conclusions

As a multifactorial ophthalmic disease, the pathological mechanisms of DR are involved in a variety of molecular signaling pathways, which have not yet been sufficiently defined. The underlying mechanisms are strongly associated with hyperglycemia-induced chronic inflammation, oxidative stress, and retinal microvascular damage. Figure 2 summarizes the integrative review findings of the present article, showing that modern medical treatment of DR mainly includes lowering blood glucose levels, anti-VEGF and anti-oxidative stress actions, laser therapy, hormonotherapy, and surgical treatment. Interestingly, Chinese medicine is an important option for DR prevention and treatment, but further research is needed to screen out the active components with pharmacological efficacy against DR from complex Chinese herbs. A limitation of the present review is that there is insufficient literature on precise details of the pathological mechanisms and pathways involved in DR. Researchers need to continue to monitor DR research results and provide updated reviews.

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