Asymmetric dimethylarginine aggravates blood–retinal barrier breakdown of diabetic retinopathy via inhibition of intercellular communication in retinal pericytes

Huang, Chuyi; Zhou, Ting; Li, Ge; Li, Mingyuan; Xiong, Xiaofang; Wu, Meiting; Jiang, Jun-Lin

doi:10.1007/s00726-019-02788-1

Cited by 10 publications

(6 citation statements)

References 34 publications

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“…These results suggested a potential beneficial effect of E. hallii in DR patients. Because the asymmetric dimethylarginine metabolite inhibited intercellular communication in retinal pericytes, it could aggravate the destruction of the blood–retinal barrier in DR and contribute to neovascularization in DR patients ( 46 , 47 ). From our correlation analysis, the associated bacteria were Odoribacter, CAG83, and merdae, whose effects need future experimental verification ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Metagenomic shotgun sequencing and metabolomic profiling identify specific human gut microbiota associated with diabetic retinopathy in patients with type 2 diabetes

Li¹,

Yang²,

Liu³

et al. 2022

Front. Immunol.

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BackgroundDiabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) and is one of the leading causes of blindness among DM patients. However, the molecular mechanism involving DR remains unclear.MethodsA case–control study with age-, sex-, and duration-matched diabetic patients and controls was conducted, which included 15 type 2 DM (T2DM) patients with DR and 15 T2DM patients without DR. Shotgun sequencing and non-targeted metabolomic profiling analyses of fecal samples were performed, and comprehensive bioinformatics analyses were conducted.ResultsUsing metagenomic analyses, we identified 293,460 unique genes in the non-DR group, while that in the DR group was 283,235, and the number of overlapping genes was 1,237,914. Regarding phylum levels, Actinobacteria decreased but Bacteroidetes increased in the DR group when compared with those in the control group. Regarding genus levels, Bifidobacterium and Lactobacillus decreased. Cellular processes, environmental information processes, and metabolism-related pathways were found at higher levels in the gut microbiome of DR patients. Using metabolomic analyses, we found 116 differentially expressed metabolites with a positive ion model and 168 differentially expressed metabolites with a negative ion model between the two groups. Kyoto Encyclopedia of Genes and Genomes annotation revealed six pathways with different levels between DR and diabetic controls, namely, cellular processes, environmental information processing, genetic information processing, human diseases, organismal systems and metabolism. Moreover, lysine biosynthesis and lysine degradation were enriched using a positive model, but histidine metabolism and β-alanine metabolism were enriched using a negative model.ConclusionsTogether, the metagenomic profiles of DR patients indicated different gut microbiota compositions and characteristic fecal metabolic phenotypes in DR patients. Our findings of microbial pathways therefore provided potential etiological and therapeutic targets for DR patients.

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Section: Discussionmentioning

confidence: 99%

Metagenomic shotgun sequencing and metabolomic profiling identify specific human gut microbiota associated with diabetic retinopathy in patients with type 2 diabetes

Li¹,

Yang²,

Liu³

et al. 2022

Front. Immunol.

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“…However, the role of cx-36 in neuronal death when neurons undergo oxygen-glucose deprivation (OGD) is unknown, not to mention its role in the neuronal protective effect of ADMA. Although ADMA has been shown to modulate the expression of other connexins, such as cx-43, cx-37, and cx-40 [ 22 ], the effect of ADMA on cx-36 is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine Protects Neurons from Oxygen Glucose Deprivation Insult by Modulating Connexin-36 Expression

Fang

Chen

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Asymmetric dimethylarginine (ADMA) is a nonselective nitric oxide synthase inhibitor. ADMA is thought to inhibit the production of nitric oxide (NO) by neurons after oxygen-glucose deprivation (OGD). The gap junction protein Connexin-36 (cx-36) is involved in the pathophysiology of stroke. We investigated whether ADMA could protect neurons from OGD insults by regulating the expression of cx-36. Methods. Cultured rat cortical neuronal cells were used. Neurons were treated with OGD with or without ADMA pretreatment. The lactate dehydrogenase (LDH) release rate was used to assess neuronal injury. Intracellular NO levels were determined using 4-amino-5-methylamino-2 ′ ,7 ′ -difluorofluorescein diacetate. Western blotting was performed to detect cx-36 expression. Results. The LDH release rate increased in the supernatant of neurons after the OGD insult, whereas ADMA treatment reduced the LDH release rate. Intracellular NO levels increased following OGD treatment, and this increase was not inhibited by ADMA treatment. Expression of cx-36 was upregulated in neurons under OGD conditions, and treatment with ADMA downregulated the expression of cx-36. Conclusions. ADMA protects neurons from OGD insult, and cx-36 downregulation may be a possible pathway involved in ADMA-mediated neuronal protection.

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“…Elevated levels of ADMA can further exacerbate oxidative stress-mediated retinal endothelial cell damage by increasing the production of ROS (64). (Figure 2) Additionally, Huang et al demonstrated that ADMA can damage the blood-retinal barrier by affecting the expression of blood-retinal barrier-specific component connexin 43 (Cx43) from diabetic rats induced by streptozotocin (STZ) (66). The disruption of the blood-retinal barrier is responsible for the formation of microaneurysms, hemorrhage, and hard exudates, which are characteristic of NPDR.…”

Section: Adma and Diabetic Retinopathymentioning

confidence: 99%

Role of ADMA in the pathogenesis of microvascular complications in type 2 diabetes mellitus

2023

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Diabetic microangiopathy is a typical and severe problem in diabetics, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic cardiomyopathy. Patients with type 2 diabetes and diabetic microvascular complications have significantly elevated levels of Asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS). ADMA facilitates the occurrence and progression of microvascular complications in type 2 diabetes through its effects on endothelial cell function, oxidative stress damage, inflammation, and fibrosis. This paper reviews the association between ADMA and microvascular complications of diabetes and elucidates the underlying mechanisms by which ADMA contributes to these complications. It provides a new idea and method for the prevention and treatment of microvascular complications in type 2 diabetes.

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Asymmetric dimethylarginine aggravates blood–retinal barrier breakdown of diabetic retinopathy via inhibition of intercellular communication in retinal pericytes

Cited by 10 publications

References 34 publications

Metagenomic shotgun sequencing and metabolomic profiling identify specific human gut microbiota associated with diabetic retinopathy in patients with type 2 diabetes

Metagenomic shotgun sequencing and metabolomic profiling identify specific human gut microbiota associated with diabetic retinopathy in patients with type 2 diabetes

Asymmetric Dimethylarginine Protects Neurons from Oxygen Glucose Deprivation Insult by Modulating Connexin-36 Expression

Role of ADMA in the pathogenesis of microvascular complications in type 2 diabetes mellitus

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