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The effects of pleiotrophin in proliferative diabetic retinopathy.

ABSTRACT: Pleiotrophin (PTN), a secreted, multifunctional cytokine, is involved in angiogenic, fibrotic and neurodegenerative diseases. However, little is known about its effects on diabetic retinopathy, a neurovascular disease. To investigate the role of PTN in proliferative diabetic retinopathy (PDR), PTN concentration in the vitreous was evaluated in PDR patients and non-diabetic controls. PTN expression was observed in epiretinal membranes from patients. PTN knockdown was performed using small interfering (si)RNA, and the effects on retinal pigment epithelium (RPE) cells and human umbilical vascular endothelia cells (HUVECs) were observed in vitro under hyperglycemic and hypoxic conditions. Cell attachment, proliferation, migration, tube formation, cell cycle, apoptosis, extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation, and VEGF levels were studied. The vitreous PTN concentration in PDR patients was higher than that in non-diabetic controls, and PTN was highly expressed in the fibrovascular membranes of PDR patients. Under hyperglycemic and hypoxic conditions, PTN knockdown reduced cell attachment, proliferation, migration, and tube formation and induced cell cycle arrest and apoptosis in vitro. Mechanically, PTN depletion decreased ERK 1/2 phosphorylation. Recombinant PTN up regulated the concentration of VEGF in vitro, which can be attenuated by the ERK 1/2 inhibitor. Taken together, our results implied that elevated PTN in PDR patients might participate in the critical processes of the development of PDR, most likely playing roles in angiogenesis and proliferation, possibly by activating the ERK 1/2 pathway and regulating VEGF secretion. These findings provide new insight into the roles of PTN in PDR and suggest that PTN may become a new target for therapeutic intervention in PDR.

SUBMITTER: Zhu X

PROVIDER: S-EPMC4305314 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The effects of pleiotrophin in proliferative diabetic retinopathy.

Zhu Xuemei X Bai Yujing Y Yu Wenzhen W Pan Chungting C Jin Enzhong E Song Dan D Xu Qiong Q Yao Yuou Y Huang Lvzhen L Tao Yong Y Li Xiaoxin X Zhao Mingwei M

PloS one 20150124 1

Pleiotrophin (PTN), a secreted, multifunctional cytokine, is involved in angiogenic, fibrotic and neurodegenerative diseases. However, little is known about its effects on diabetic retinopathy, a neurovascular disease. To investigate the role of PTN in proliferative diabetic retinopathy (PDR), PTN concentration in the vitreous was evaluated in PDR patients and non-diabetic controls. PTN expression was observed in epiretinal membranes from patients. PTN knockdown was performed using small interfe ...[more]

PMID: 25617851

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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.

Project description:To establish adaptive optics scanning laser ophthalmoscopy as a method to detect and characterize microscopic signs of diabetic retinopathy in capillaries and cone photoreceptors in the parafovea.Recently, adaptive optics scanning laser ophthalmoscope (AOSLO) has enabled noninvasive assessment of photoreceptors, capillaries, and leukocytes in the retinas of live human subjects. Repeated application of AOSLO imaging along with comparison to fluorescein angiography was used to track individual capillaries near the foveal avascular zone (FAZ) from one eye affected with severe non-proliferative diabetic retinopathy. Fluorescein angiography was used to identify clinical signs of diabetic retinopathy, such as microaneurysms and intraretinal microvascular abnormalities, and corresponding regions were imaged and assessed using the AOSLO. In addition, the structural integrity of photoreceptors and the spatial distribution of leukocytes around the parafoveal capillary network were quantitatively assessed.Capillaries and cone photoreceptors were visualized using the AOSLO without the use of injected contrast agents. Although the majority of capillaries were stable over a period of 16 months, one capillary at the edge of the FAZ dropped out, leading to a small but significant increase in FAZ size. Longitudinal assessment of the capillaries also showed microaneurysm formation and disappearance as well as the formation of tiny capillary bends similar in appearance to intraretinal microvascular abnormalities. The leukocytes in the capillary network were found to preferentially travel through the same routes in all four visits, suggesting that these channels are robust against small changes to the surrounding capillaries. In this eye, cone photoreceptor spacing was increased in the fovea when compared with normal data but stable across all visits.AOSLO imaging can be used to longitudinally track capillaries, leukocytes, and photoreceptors in diabetic retinopathy. Capillary changes that can be detected include dropout of individual capillaries as well as formation and disappearance of microaneurysms.

Dataset Information

The effects of pleiotrophin in proliferative diabetic retinopathy.

Publications

The effects of pleiotrophin in proliferative diabetic retinopathy.

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