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Proliferative diabetic retinopathy transcriptomes reveal angiogenesis, anti-angiogenic therapy escape mechanisms, fibrosis and lymphatic involvement.

ABSTRACT: Proliferative diabetic retinopathy (PDR) is a sight-threatening diabetic complication in urgent need of new therapies. In this study we identify potential molecular mechanisms and target candidates in the pathogenesis of PDR fibrovascular tissue formation. We performed mRNA sequencing of RNA isolated from eleven excised fibrovascular membranes of type 1 diabetic PDR patients and two non-diabetic patients with rhegmatogenous retinal detachment with proliferative vitreoretinopathy. We determined differentially expressed genes between these groups and performed pathway and gene ontology term enrichment analyses to identify potential underlying mechanisms, pathways, and regulators. Multiple pro-angiogenic processes, including VEGFA-dependent and -independent pathways, as well as processes related to lymphatic development, epithelial to mesenchymal transition (EMT), wound healing, inflammation, fibrosis, and extracellular matrix (ECM) composition, were overrepresented in PDR. Overrepresentation of different angiogenic processes may help to explain the transient nature of the benefits that many patients receive from current intravitreal anti-angiogenic therapies, highlighting the importance of combinatorial treatments. Enrichment of genes and pathways related to lymphatic development indicates that targeting lymphatic involvement in PDR progression could have therapeutic relevance. Together with overrepresentation of EMT and fibrosis as well as differential ECM composition, these findings demonstrate the complexity of PDR fibrovascular tissue formation and provide avenues for the development of novel treatments.

SUBMITTER: Korhonen A

PROVIDER: S-EPMC8458546 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProliferative diabetic retinopathy (PDR), a sight-threatening retinopathy, is the leading cause of irreversible blindness in adults. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop PDR, suggesting the existence of other potential pathogenic factors underlying PDR. This study aimed to investigate the plasma metabotype of patients with PDR and to identify novel metabolite markers for PDR. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of diabetic retinopathy.MethodsA total of 1024 patients with type 2 diabetes were screened. To match clinical parameters between case and control subjects, patients with PDR (PDR, n = 21) or those with a duration of diabetes of ≥10 years but without diabetic retinopathy (NDR, n = 21) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS).ResultsThe distinct metabolites between PDR and NDR groups were significantly enriched in 9 KEGG pathways (P < 0.05, impact > 0.1), namely, alanine, aspartate and glutamate metabolism, caffeine metabolism, beta-alanine metabolism, purine metabolism, cysteine and methionine metabolism, sulfur metabolism, sphingosine metabolism, and arginine and proline metabolism. A total of 63 altered metabolites played important roles in these pathways. Finally, 4 metabolites were selected as candidate biomarkers for PDR, namely, fumaric acid, uridine, acetic acid, and cytidine. The area under the curve for these biomarkers were 0.96, 0.95, 1.0, and 0.95, respectively.ConclusionsThis study suggested that impairment in the metabolism of pyrimidines, arginine and proline were identified as metabolic dysregulation associated with PDR. And fumaric acid, uridine, acetic acid, and cytidine might be potential biomarkers for PDR. Fumaric acid was firstly reported as a novel metabolite marker with no prior reports of association with diabetes or diabetic retinopathy, which might provide insights into potential new pathogenic pathways for diabetic retinopathy.

Project description:IntroductionFew qualitative studies have explored the patient experience of daily life with proliferative diabetic retinopathy (PDR) and associated treatments. Herein, a conceptual model was developed to comprehensively examine symptoms, functional impacts, and treatment experiences in PDR.MethodsA qualitative, mixed-methods study comprising a literature search and semi-structured interviews with clinicians and patients was conducted. Published literature and online patient resources were searched to identify concepts relevant to patients, including symptoms, functional impacts, and treatment experiences of PDR. Semi-structured interviews with experienced clinicians were conducted to identify symptoms and impacts reported by patients with PDR and to receive feedback regarding concepts identified from the literature search. A preliminary conceptual model was then developed based on findings from the literature search and clinician interviews. Patients with PDR participated in two rounds of semi-structured interviews to identify additional concepts relevant to the patient experience in PDR and associated treatments, which informed revisions to the conceptual model. Saturation of patient interviews was assessed.ResultsFindings from the literature search and clinician interviews yielded 109 concepts that were included in a preliminary conceptual model with three overarching domains: symptoms, impacts, and managing the disease. Clinicians confirmed concepts identified from the literature search. During interviews, patients reported a broad spectrum of symptoms (e.g., red vision); functional impacts relating to activities of daily living (e.g., reading), emotional functioning (e.g., loss of independence), and social functioning (e.g., problems recognizing faces); and treatment experiences (e.g., improves eye problems, no change) associated with PDR. Additional concepts elicited in patient interviews informed revisions to the conceptual model. Saturation was achieved in the patient sample.ConclusionsA wide variety of symptoms, functional impacts, and treatment experiences that significantly affect health-related quality of life were identified in patients with PDR. These insights are critical for understanding PDR symptomology and assessing treatment response.

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Proliferative diabetic retinopathy transcriptomes reveal angiogenesis, anti-angiogenic therapy escape mechanisms, fibrosis and lymphatic involvement.

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