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Diabetic retinopathy remains a relevant clinical problem. In parallel with diagnostic and therapeutic improvements, the role of glycaemia and reactive metabolites causing cell stress and biochemical abnormalities as treatment targets needs continuous re-evaluation. Furthermore, the basic mechanisms of physiological angiogenesis, remodelling and pruning give important clues about the origins of vasoregression during the very early stages of diabetic retinopathy and can be modelled in animals. This review summarises evidence supporting a role for the neurovascular unit—composed of neuronal, glial and vascular cells—as a responder to the biochemical changes imposed by reactive metabolites and high glucose. Normoglycaemic animal models developing retinal degeneration, provide valuable information about common pathways downstream of progressive neuronal damage that induce vasoregression, as in diabetic models. These models can serve to assess novel treatments addressing the entire neurovascular unit for the benefit of early diabetic retinopathy.

Chronic kidney disease (CKD) is a progressive systemic disease, which changes the function and structure of the kidneys irreversibly over months or years. The final common pathological manifestation of chronic kidney disease is renal fibrosis and is characterized by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. In recent years, numerous studies have reported the therapeutic benefits of natural products against modern diseases. Substantial attention has been focused on the biological role of polyphenols, in particular flavonoids, presenting broadly in plants and diets, referring to thousands of plant compounds with a common basic structure. Evidence-based pharmacological data have shown that flavonoids play an important role in preventing and managing CKD and renal fibrosis. These compounds can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress and inflammation. In this review, we summarize the function and beneficial properties of common flavonoids for the treatment of CKD and the relative risk factors of CKD.

Diabetic retinopathy (DR) is characterized by vasoregression and glial activation. miRNA-124 (miR-124) reduces retinal microglial activation and alleviates vasoregression in a neurodegenerative rat model. Our aim was to determine whether miR-124 affects vascular and neural damage in the early diabetic retina. Diabetes was induced in 8-week-old Wistar rats by streptozotocin (STZ) injection. At 16 and 20 weeks, the diabetic rats were intravitreally injected with miR-124 mimic, and retinae were analyzed at 24 weeks. Microvascular damage was identified by evaluating pericyte loss and acellular capillary (AC) formation. Müller glial activation was assessed by glial fibrillary acidic protein (GFAP) immunofluorescence staining. Microglial activation was determined by immunofluorescent staining of ionized calcium-binding adaptor molecule 1 (Iba1) in whole mount retinae. The neuroretinal function was assessed by electroretinography. The expression of inflammation-associated genes was evaluated by qRT-PCR. A wound healing assay was performed to quantitate the mobility of microglial cells. The results showed that miR-124 treatment alleviated diabetic vasoregression by reducing AC formation and pericyte loss. miR-124 blunted Müller glial- and microglial activation in diabetic retinae and ameliorated neuroretinal function. The retinal expression of inflammatory factors including Tnf-α, Il-1β, Cd74, Ccl2, Ccl3, Vcam1, Tgf-β1, Arg1, and Il-10 was reduced by miR-124 administration. The elevated mobility of microglia upon high glucose exposure was normalized by miR-124. The expression of the transcription factor PU.1 and lipid raft protein Flot1 was downregulated by miR-124. In rat DR, miR-124 prevents vasoregression and glial activation, improves neuroretinal function, and modulates microglial activation and inflammatory responses.

To assess the prevalence and risk factors for early and severe diabetic retinopathy and macular edema in a large cohort of patients with type 2 diabetes Retinopathy grading (any retinopathy, severe retinopathy, diabetic macular edema) and risk factors of 64784 were prospectively recorded between January 2000 and March 2013 and analyzed by Kaplan-Meier analysis and logistic regression. Retinopathy was present in 20.12% of subjects, maculopathy was found in 0.77%. HbA1c > 8%, microalbuminuria, hypertension, BMI > 35 kg/m2 and male sex were significantly associated with any retinopathy, while HbA1c and micro- and macroalbuminuria were the strongest risk predictors for severe retinopathy. Presence of macroalbuminuria increased the risk for DME by 177%. Retinopathy remains a significant clinical problem in patients with type 2 diabetes. Metabolic control and blood pressure are relevant factors amenable to treatment. Concomitant kidney disease identifies high risk patients and should be emphasized in interdisciplinary communication.

A product of the soluble epoxide hydrolase enzyme, 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP), is implicated in the pathogenesis of diabetic retinopathy; levels of 19,20-DHDP increase in the retinas of mice and humans with diabetes, and inhibition of its production can rescue vascular abnormalities in a mouse model of the disease. Rescuing diabetic retinas Untreated diabetes can cause vascular complications including diabetic retinopathy—a progressive loss of retinal vascular cells that causes vessel leakiness, retinal oedema and, ultimately, blindness. Ingrid Fleming and colleagues found that a bioactive lipid derived from docosahexaenoic acid (19,20-DHDP) is implicated in the pathogenesis of this vascular disease. They show that the levels of 19,20-DHDP increase in the retinas of diabetic mice and humans, and that inhibiting the production of this lipid can rescue vascular abnormalities in a mouse model of diabetic retinopathy. The authors suggest that the mechanism that underlies the effect of 19,20-DHDP is an alteration of the dynamics of vascular cell membranes, which affects cell–cell junctions. Diabetic retinopathy is an important cause of blindness in adults 1 , 2 , and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema 3 . Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization 4 , 5 . Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte–endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes and is the most common cause of end stage renal disease (ESRD). Renal fibrosis is the final pathological change in DN. It is widely believed that cellular phenotypic switching is the cause of renal fibrosis in diabetic nephropathy. Several types of kidney cells undergo activation and differentiation and become reprogrammed to express markers of mesenchymal cells or podocyte-like cells. However, the development of targeted therapy for DN has not yet been identified. Here, we discussed the pathophysiologic changes of DN and delineated the possible origins that contribute to myofibroblasts and podocytes through phenotypic transitions. We also highlight the molecular signaling pathways involved in the phenotypic transition, which would provide valuable information for the activation of phenotypic switching and designing effective therapies for DN.

This study aimed to characterize the role of female sex in the pathogenesis of diabetic retinopathy. In the retinae of female Ins2Akita -diabetic mice (F-IA), ovariectomized female Ins2Akita -diabetic mice (F-IA/OVX), male Ins2Akita -diabetic mice (M-IA), and female STZ-diabetic mice (F-STZ), the formation of reactive metabolites and post-translational modifications, damage to the neurovascular unit, and expression of cellular stress response genes were analyzed. Compared to the male diabetic retina, the concentrations of the glycation adduct fructosyl-lysine, the Maillard product 3-deoxyglucosone, and the reactive metabolite methylglyoxal were significantly reduced in females. In females, there was also less evidence of diabetic damage to the neurovascular unit, as shown by decreased pericyte loss and reduced microglial activation. In the male diabetic retina, the expression of several members of the crystallin gene family (Cryab, Cryaa, Crybb2, Crybb1, and Cryba4) was increased. Clinical data from type 1 diabetic females showed that premenopausal women had a significantly lower prevalence of diabetic retinopathy compared to postmenopausal women stratified for disease duration and glycemic control. These data emphasize the importance of estradiol in protecting the diabetic retina and highlight the pathogenic relevance of sex in diabetic retinopathy.

Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear. Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software. Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans. Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.

Aims/hypothesis The aim of this study was to evaluate damage to the neurovascular unit in a mouse model of hyperglycaemic memory. Methods A streptozotocin-induced mouse model of diabetes (C57BL/6J background) received insulin-releasing pellets and pancreatic islet-cell transplantation. Damage to the neurovascular unit was studied by quantitative retinal morphometry for microvascular changes and microarray analysis, with subsequent functional annotation clustering, for changes of the retinal genome. Results Sustained microvascular damage was confirmed by persistent loss of pericytes in the retinal vasculature (PC/mm 2 ): compared with healthy controls (1981 ± 404 PC/mm 2 ), the pericyte coverage of the retinal vasculature was significantly reduced in diabetic mice (1571 ± 383 PC/mm 2 , p  < 0.001) and transplanted mice (1606 ± 268 PC/mm 2 , p  < 0.001). Genes meeting the criteria for hyperglycaemic memory were attributed to the cytoskeletal and nuclear cell compartments of the neurovascular unit. The most prominent regulated genes in the cytoskeletal compartment were Ddx51 , Fgd4 , Pdlim7 , Utp23 , Cep57 , Csrp3 , Eml5 , Fhl3 , Map1a , Mapk1ip1 , Mnda , Neil2 , Parp2 , Myl12b , Dynll1 , Stag3 and Sntg2 , and in the nuclear compartment were Ddx51 , Utp23 , Mnda , Kmt2e , Nr6a1 , Parp2 , Cdk8 , Srsf1 and Zfp326 . Conclusions/interpretation We demonstrated that changes in gene expression and microvascular damage persist after euglycaemic re-entry, indicating memory. Data availability The datasets generated during and/or analysed during the current study are available in the GEO repository, GSE87433, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=idmbysgctluxviv&acc=GSE87433 .