One of the typical features of DR is hyperglycemia, especially fluctuations in serum glucose, which damage endothelial cells [20]. Thus, a high level of blood glucose is considered to play an essential role in the development of DR. Based on the dietary habits of populations living in Xinjiang that exhibit a high incidence of DM and DR, we attempted to explore the role of dyslipidemia in the development of DR. In this study, RF/6A cells were used to imitate the pathogenesis of DR under high-fat conditions. Similar to other previous reports, our results showed that high glucose induced an angiogenic response in RF/6A cells based on increased cell migration [21, 22], which was affected by ox-LDL; at a low concentration, this effect was enhanced, whereas at a high concentration, the effect was suppressed (Fig. 1–3).
Previous reports demonstrated that LOX-1 expression is significantly increased in retinal endothelial cells under high-glucose conditions and in the retinas of diabetic rats [23, 24]. Our previous data also showed that high-glucose conditions led to upregulation of LOX-1 expression. More importantly, our current results showed that the protein expression of LOX-1 was increased in RF/6A cells following ox-LDL and glucose treatment. Interestingly, when cells were treated with ox-LDL and high glucose, only a lower ox-LDL concentration (25 µg and 50 µg) increased the expression of LOX-1. Therefore, the present findings illustrate the combined effects of dyslipidemia and hyperglycemia on expression of this receptor. This phenomenon may be explained by the mechanism of vascular endothelial damage [25, 26].
Several factors such as shear stress [26] and advanced glycation end-products [27], especially ox-LDL, can upregulate LOX-1. The activation of this receptor induces the production of adhesion molecules, and thus we chose adhesion molecule ICAM-1 to study the related mechanism. ICAM-1, also known as CD54, belongs to the immunoglobulin super family (IgSF) of adhesion molecules and is an important adhesion molecule that mediates adhesion reaction [28]. ICAM-1 is expressed at a low level on resting VEC and exerts its biological activity through binding with specific receptors on the surface of VEC [29]. As a transmembrane protein of endothelial cells, ICAM-1 is vital for stabilization of intercellular interactions and promotion of leukocyte and endothelial cell migration [30, 31].
In the process of AS, ox-LDL/LOX-1 is the primary factor that mediates endothelial dysfunction [32]. The mechanism similarities between DR and AS lies in the presence of VEC damage. Risk factors such as high-fat diet trigger the expression of adhesion molecules and promote the attachment of leukocytes to endothelial cells at low flow [33]. ICAM-1, as one of the major mediators of leukocyte adhesion, is induced by ox-LDL in endothelial cells [34]. Our present study showed that ox-LDL can induce LOX-1 expression and upregulate ICAM-1 expression in a high-glucose environment. These results seemingly contrast with a previous study in which mice overexpressing LOX-1 in endothelial cells showed increased ICAM-1 expression in the presence of ox-LDL [35]; the difference may be related to the combined effects of high fat and high glucose. Uyghurs and Kazakhs, the two largest minority groups in Xinjiang, share similar dietary habits, mainly involving lamb, dairy products, and pasta, which contains a high amount of carbohydrates. Meanwhile, beef and mutton, which are very popular among Uyghurs and Kazakhs, are rich in saturated fatty acids, providing sufficient material for the synthesis of fats in the body.
In summary, our results demonstrate that a certain concentration of ox-LDL induced retinal vascular endothelial injury by blocking ICAM-1 expression in a high-glucose environment. This suggests that dyslipidemia plays an important role in the development of DR and also emphasizes the importance of active regulation of blood lipids in DR therapy, providing insight into prevention and treatment strategies for DR.