TranslationalLow blood and vitreal BDNF, LXA4 and altered Th1/Th2 cytokine balance are potential risk factors for diabetic retinopathy
Introduction
Type 2 diabetes mellitus as well as its complication namely diabetic retinopathy is low-grade systemic inflammatory condition [1], [2]. Diabetic retinopathy shows characteristic proliferative response of the endothelium to glucose-induced toxicity, owing to uncontrolled hyperglycemia of long duration. Diabetic proliferative retinopathy not only involves proliferation of endothelial cells (ECs) but also involves migration of smooth muscle cells and neoangiogenesis [3]. An important growth factor that plays a significant role in angiogenesis is vascular endothelial growth factor (VEGF). The initial stimulant to trigger VEGF expression may reside in hyperglycemia [4], that is subsequently sustained by other stimuli, including advanced glycation end products [5] and reactive oxygen intermediates [6], all of which further increase VEGF expression. These results imply that diabetic retinopathy is an inflammatory condition [7], [8]. Though classical clinical features of inflammation are not present in the retina, microscopic features of inflammation such as vessel dilatation, altered flow, exudation of fluids, including plasma proteins, and leukocyte infiltration are seen in diabetic retinopathy [8], [9]. The low-grade chronic inflammation that is associated with insulin resistance in type 2 DM which along with increasing advance glycation end products and ROS generation can lead to hypoxia that results in microvascular and other diabetic complications [10]. PEDF is a multifunctional protein with neurotrophic and antiangiogenic properties [11]. VEGF/PEDF ratio is characteristically increased in DR [12]. The blood levels of PEDF are reported to be increased in diabetes mellitus, while the vitreous levels are lowered in DR [13], [14]. Resolution of inflammation is a process that usually sets in during inflammation, wherein the system attempts for a homeostasis between the pro- and anti-inflammatory mediators. Lipoxin A4 (LXA4) is a key mediator of this resolution process that is known to inhibit leukocyte activation, free radical generation and chemotactic responses of polymorphonuclear neutrophils and activation of monocytes and macrophages [15]. Lipoxin are protective anti-inflammatory lipid mediators, as shown in several experimental models of diseases such as inflammatory bowel diseases, periodontal disease, and cardiovascular disease [16], [17]. It has also been shown that lipoxins attenuate diabetes related pathologies, such as diabetic nephropathy and metabolic syndrome which involves adipose inflammation [18], [19]. Pretreatment with LXA4 of endothelial cells (HUVEC) decreased VEGF-stimulated VEGF receptor 2 (KDR/FLK-1) phosphorylation and downstream signaling events [20].
Brain-derived neurotrophic factor (BDNF) is an important transmitter of signals between the immune and the nervous system. BDNF reportedly modulates local inflammation in brain tissues at the level of cellular cytokines, and expression of transcription factors in ischemic stroke conditions [21]. BDNF binds to the TrkB receptor expressed abundantly in hippocampus and cerebral cortex region of the brain [21]. BDNF plays a crucial role in modulating energy homeostasis [22]. Administration of BDNF decreases the food intake, increases the energy expenditure and ameliorates hyperinsulinemia as well as hyperglycemia in diabetic db/db mice [23], [24]. A significant reduction of BDNF at the level of protein and mRNA, in diabetic rat retina positively correlating with degeneration of dopaminergic amacrine cells has been reported [25]. Similar reduction of BDNF levels in diabetic mice has been associated with impaired visual function [26]. Murine astrocyte cultures showed that prostaglandins D2 and E2, derived from membrane arachidonic acid are proinflammatory mediators that induce nerve growth factors and BDNF [27], suggesting that BDNF levels are possibly, inversely associated with inflammatory status. Previously, we reported that a close interaction exists between BDNF and PUFAs including their anti-inflammatory metabolites such as lipoxins and resolvins [28]. The present study was designed to estimate serum and vitreous levels of BDNF, LXA4, and Th1/Th2 cytokines in type 2 diabetes mellitus (DM) and look for changes if any, associated with diabetic retinopathy (DR). In addition, we also examined the BDNF and LXA4 exposure on LPS induced proinflammatory state in ARPE 19 cells.
Section snippets
Materials and Methods
As part of a three year IRB approved pilot study at a tertiary care ophthalmic center in south Indian population, 114 individuals were recruited in the study after informed consent. All experiments involving human subjects adhered to the tenets of the Declaration of Helsinki. All the cases in the study were type 2 DM. Of the cases recruited, 27 were type 2 DM with no retinopathy (mean age: 51 ± 13 years; 17 M, 10), 30 cases were non proliferative diabetic retinopathy (NPDR) (mean age: 58 ± 10 years 20
Changes in the levels of biochemical parameters in control and diabetic groups
Plasma glucose, HbA1c, μ-albumin, serum lipid profile and glucose levels were measured in all the four groups in the study. Among all the parameters examined, HbA1c, triglycerides, TC/HDL-C ratio, and urine μ-albumin were significantly elevated showing increasing trend with disease progression from DM to NPDR and PDR (Table 1). Demographic and clinical details of the study subjects are shown in Supplementary Table 1 (a–d).
Serum BDNF, VEGF, PEDF and plasma LXA4 levels in control and diabetic groups
Table 2a shows that the serum BDNF level was reduced significantly in
Discussion
Inflammatory changes appear to play a significant role in the pathogenesis of diabetic retinopathy. The inflammatory cytokines modulated by growth factors can have a net pro- or anti-inflammatory effect [29]. Activation of NF-κB induces the expression of ICAM-1 and iNOS, release of prostaglandins and cytokines, contributing to degeneration of retinal capillaries [30]. In the present study, vitreous level of VEGF and PEDF was increased significantly in PDR compared to Macular Hole as previously
Author Contributions
This study was designed by AN and UD. Data were acquired by KK, JM, SS, TS and AMM and interpreted by AK, KK and JM. The manuscript was written by KK and AN; and reviewed and approved by all authors.
Funding
This study was funded by the Department of Biotechnology, Government of India (DBT No. BT/PR11627/MED/30/157/2008). Dr. U N Das was in receipt of Ramalingaswami Fellowship of the Department of Biotechnology, New Delhi, India during the tenure of this study. This study was partly funded, by grants from the Department of Science and Technology (No. IR/SO/LU/03/2008/1) under Intensification of Research in High Priority Areas (IRPHA).
Conflict of Interest
The authors have no potential conflicts of interests to declare.
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