Specialized Pro-resolving Lipid Mediators: Modulation of Diabetes-Associated Cardio-, Reno-, and Retino-Vascular Complications

Abstract

Diabetes and its associated chronic complications present a healthcare challenge on a global scale. Despite improvements in the management of chronic complications of the micro-/macro-vasculature, their growing prevalence and incidence highlights the scale of the problem. It is currently estimated that diabetes affects 425 million people globally and it is anticipated that this figure will rise by 2025 to 700 million people. The vascular complications of diabetes including diabetes-associated atherosclerosis and kidney disease present a particular challenge. Diabetes is the leading cause of end stage renal disease, reflecting fibrosis leading to organ failure. Moreover, diabetes associated states of inflammation, neo-vascularization, apoptosis and hypercoagulability contribute to also exacerbate atherosclerosis, from the metabolic syndrome to advanced disease, plaque rupture and coronary thrombosis. Current therapeutic interventions focus on regulating blood glucose, glomerular and peripheral hypertension and can at best slow the progression of diabetes complications. Recently advanced knowledge of the pathogenesis underlying diabetes and associated complications revealed common mechanisms, including the inflammatory response, insulin resistance and hyperglycemia. The major role that inflammation plays in many chronic diseases has led to the development of new strategies aiming to promote the restoration of homeostasis through the “resolution of inflammation.” These strategies aim to mimic the spontaneous activities of the ‘specialized pro-resolving mediators’ (SPMs), including endogenous molecules and their synthetic mimetics. This review aims to discuss the effect of SPMs [with particular attention to lipoxins (LXs) and resolvins (Rvs)] on inflammatory responses in a series of experimental models, as well as evidence from human studies, in the context of cardio- and reno-vascular diabetic complications, with a brief mention to diabetic retinopathy (DR). These data collectively support the hypothesis that endogenously generated SPMs or synthetic mimetics of their activities may represent lead molecules in a new discipline, namely the ‘resolution pharmacology,’ offering hope for new therapeutic strategies to prevent and treat, specifically, diabetes-associated atherosclerosis, nephropathy and retinopathy.

Resolvin D1 Modulates the Intracellular VEGF-Related miRNAs of Retinal Photoreceptors Challenged With High Glucose

“…Besides a variety of pre-clinical and clinical studies, no drugs have been approved for treatment of non-proliferative diabetic retinopathy (NPDR) so far. Recently, treatment with ω3-PUFA and pro-resolving lipid mediators has been investigated in experimental studies (Das, 2013;Wang and Daggy, 2017;de Gaetano et al, 2018) as novel therapeutic strategy in DR. Among the pro-resolving mediators, resolvin D1 (RvD1) has emerged as the most promising alternative anti-inflammatory drug for treatment of DR.…”

The Effects of Salvianolate Combined With Western Medicine on Diabetic Nephropathy: A Systematic Review and Meta-Analysis

“…Its pathogenesis may be linked to renal hyperfiltration and renal injury, glucose metabolic disorder, vasoactive substances, and heredity (Bhattacharjee et al, 2016). Chronic inflammatory response and oxidative stress also play important roles on DN and have become appropriate targets for therapeutic intervention (Tziomalos and Athyros, 2015;de Gaetano et al, 2018). According to Mogensen Stage, DN can be divided into five stages.…”

Resolvin D1 reduces mitochondrial damage to photoreceptors of primary retinal cells exposed to high glucose

“…They create an early stage of inflammation that predisposes the cells to a hormetic response in which defensive, anti‐inflammatory, and proresolving mediators and mechanisms are activated (Maisto et al, ; Rossi et al, ). Therefore, although anti‐tumor necrosis factor α and anti‐vascular endothelial growth factor are the standard anti‐inflammatory approach for DR, novel pro‐resolving mediators based strategies have been recently considered in several DR experimental models (Das, ; de Gaetano et al, ; Wang & Daggy, ). One of these strategies involves the proresolving lipid mediator RVD1.…”

“…Therefore, although anti-tumor necrosis factor α and anti-vascular endothelial growth factor are the standard anti-inflammatory approach for DR, novel pro-resolving mediators based strategies have been recently considered in several DR experimental models (Das, 2013;de Gaetano et al, 2018;Wang & Daggy, 2017). One of these strategies involves the proresolving lipid mediator RVD1.…”