Diabetic retinopathy: Involved cells, biomarkers, and treatments

Ren, Jiahui; Zhang, Shuxia; Pan, Yuwei; Jin, Meiqi; Li, Jiaxin; Luo, Yun; Sun, Xiaobo; Li, Guang

doi:10.3389/fphar.2022.953691

Cited by 36 publications

(36 citation statements)

References 217 publications

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“…Diabetic retinopathy (DR), an incurable eye disease caused by prolonged high glucose levels is a leading complication of diabetes mellitus and a common cause of blindness amongst working age adults ( 1 ). DR has been defined as a microvascular disease characterized by microaneurysms, intraretinal hemorrhaging, deposition of hard and soft exudates and abnormal angiogenesis ( 2 ). However, DR is also a neurodegenerative and neuroinflammatory disorder.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological depletion of microglia alleviates neuronal and vascular damage in the diabetic CX3CR1-WT retina but not in CX3CR1-KO or hCX3CR1I249/M280-expressing retina

et al. 2023

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Diabetic retinopathy, a microvascular disease characterized by irreparable vascular damage, neurodegeneration and neuroinflammation, is a leading complication of diabetes mellitus. There is no cure for DR, and medical interventions marginally slow the progression of disease. Microglia-mediated inflammation in the diabetic retina is regulated via CX3CR1-FKN signaling, where FKN serves as a calming signal for microglial activation in several neuroinflammatory models. Polymorphic variants of CX3CR1, hCX3CR1I249/M280, found in 25% of the human population, result in a receptor with lower binding affinity for FKN. Furthermore, disrupted CX3CR1-FKN signaling in CX3CR1-KO and FKN-KO mice leads to exacerbated microglial activation, robust neuronal cell loss and substantial vascular damage in the diabetic retina. Thus, studies to characterize the effects of hCX3CR1I249/M280-expression in microglia-mediated inflammation in the diseased retina are relevant to identify mechanisms by which microglia contribute to disease progression. Our results show that hCX3CR1I249/M280 mice are significantly more susceptible to microgliosis and production of Cxcl10 and TNFα under acute inflammatory conditions. Inflammation is exacerbated under diabetic conditions and coincides with robust neuronal loss in comparison to CX3CR1-WT mice. Therefore, to further investigate the role of hCX3CR1I249/M280-expression in microglial responses, we pharmacologically depleted microglia using PLX-5622, a CSF-1R antagonist. PLX-5622 treatment led to a robust (~70%) reduction in Iba1+ microglia in all non-diabetic and diabetic mice. CSF-1R antagonism in diabetic CX3CR1-WT prevented TUJ1+ axonal loss, angiogenesis and fibrinogen deposition. In contrast, PLX-5622 microglia depletion in CX3CR1-KO and hCX3CR1I249/M280 mice did not alleviate TUJ1+ axonal loss or angiogenesis. Interestingly, PLX-5622 treatment reduced fibrinogen deposition in CX3CR1-KO mice but not in hCX3CR1I249/M280 mice, suggesting that hCX3CR1I249/M280 expressing microglia influences vascular pathology differently compared to CX3CR1-KO microglia. Currently CX3CR1-KO mice are the most commonly used strain to investigate CX3CR1-FKN signaling effects on microglia-mediated inflammation and the results in this study indicate that hCX3CR1I249/M280 receptor variants may serve as a complementary model to study dysregulated CX3CR1-FKN signaling. In summary, the protective effects of microglia depletion is CX3CR1-dependent as microglia depletion in CX3CR1-KO and hCX3CR1I249/M280 mice did not alleviate retinal degeneration nor microglial morphological activation as observed in CX3CR1-WT mice.

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Section: Introductionmentioning

confidence: 99%

Pharmacological depletion of microglia alleviates neuronal and vascular damage in the diabetic CX3CR1-WT retina but not in CX3CR1-KO or hCX3CR1I249/M280-expressing retina

et al. 2023

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“…Furthermore, evidence have shown that inflammatory mediators initially rise in the retina and then enter the vitreous (12), implying the early predictive role of biomarkers in retina. Several monocyte/ macrophage markers (e.g.,F4/80mRNA, CCL2) and glial cells markers (e.g.,NF-kB, IL-17) in retina are found correlated with the progression of DR in rat models (8), which need further confirmation in clinical practice.…”

Section: Inflammatory Biomarkersmentioning

confidence: 85%

“…Besides, proteomics analysis from tears of DR patients uncovered multiple proteins changed correlating with the occurrence and severity of DR, providing evidence and targets for tear-based protein biomarkers for early diagnosis of DR (23). Furthermore, non-coding RNAs, especially microRNAs, are also the most well-studied biomarkers of DR (8). MicroRNAs have been shown to regulate multiple pathological processes during DR, including cell proliferation, apoptosis, inflammation and microcirculation impairments and exerted differential expressions in blood and vitreous samples from DR patients (24,58).…”

Section: Multi-omics Related Biomarkersmentioning

confidence: 99%

Novel biomarkers and therapeutic approaches for diabetic retinopathy and nephropathy: Recent progress and future perspectives

Xie

Xiao

2022

Front. Endocrinol.

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The global burden due to microvascular complications in patients with diabetes mellitus persists and even increases alarmingly, the intervention and management are now encountering many difficulties and challenges. This paper reviews the recent advancement and progress in novel biomarkers, artificial intelligence technology, therapeutic agents and approaches of diabetic retinopathy and nephropathy, providing more insights into the management of microvascular complications.

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“…Rats in the diabetic + IMD-0354 group were administrated IMD-0354 (30 mg/kg) intraperitoneally from week 6 of STZ injection for 6 consecutive weeks through the termination of the experiment. Rats in the control + IMD-0354 group were also given IMD-0354 (30 mg/kg) for six consecutive weeks, in order to assess the drug’s safety and potential side effects ( 1 ). Normal control and one group of diabetic rats received the same volume of 4% DMSO in phosphate-buffered saline (PBS; Gibco, Grand Island, NY, USA) at each time point.…”

Section: Methodsmentioning

confidence: 99%

“…The most common microvascular complication of diabetes is diabetic retinopathy (DR). It is one of the leading causes of blindness in the working age population worldwide ( 1 ). DR has been considered as a microangiopathy with major pathological manifestations, including progressive destruction of the internal blood-retinal barrier, pericytes loss, and the development of microhemangioma.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats

Ding¹,

Sun²,

Guo³

et al. 2023

Ann Transl Med

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Background To determine the anti-inflammatory effects of IMD-0354, a specific NF-κB blocker, on glial cells in rats with streptozotocin (STZ)-induced diabetic retinopathy (DR). Methods The following four groups of rats were used: control, control + IMD-0354, STZ, and STZ + IMD-0354. After six weeks of STZ injection, diabetic rats and nondiabetic control rats received IMD-0354 (30 mg/kg) or an equal volume of 4% dimethyl sulfoxide (DMSO) in phosphate-buffered saline intraperitoneally for six consecutive weeks. The following four groups of primary rat retinal microglia and Müller cells were used: control (5 mM), control + IMD-0354, high glucose (20 mM), and high glucose + IMD-0354. The effects of IMD-0354 on nuclear factor-κB (NF-κB) activation, oxidative stress strength, expression of inflammatory cytokines and VEGF (vascular endothelial growth factor), activation of glial cells, and apoptosis of neuron cells were evaluated by immunohistochemistry, oxidative stress assays, western blot, enzyme linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining respectively. Results Nuclear translocation of NF-κB was markedly increased in diabetic rat retina and high glucose treated glial cells. Systemic administration of IMD-0354 significantly inhibited NF-κB activation in both diabetic rat retina and high glucose treated glial cells, ameliorated oxidative injury, inflammatory responses, VEGF production and glial cell activation, and protected neurons from apoptosis. Conclusions Our findings indicated that NF-κB activation is acritical step in the abnormal reactivity of glial cells in STZ-induced diabetic rats. Inhibition effect of IMD-0354 on NF-κB activation may represent a promising therapeutic strategy for DR via a variety of mechanisms, including inflammation reduction and glial cells regulation.

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Diabetic retinopathy: Involved cells, biomarkers, and treatments

Cited by 36 publications

References 217 publications

Pharmacological depletion of microglia alleviates neuronal and vascular damage in the diabetic CX3CR1-WT retina but not in CX3CR1-KO or hCX3CR1I249/M280-expressing retina

Pharmacological depletion of microglia alleviates neuronal and vascular damage in the diabetic CX3CR1-WT retina but not in CX3CR1-KO or hCX3CR1I249/M280-expressing retina

Novel biomarkers and therapeutic approaches for diabetic retinopathy and nephropathy: Recent progress and future perspectives

Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats

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