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A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression.

ABSTRACT: Diabetic retinopathy (DR) is a major complication of diabetes mellitus, and is the leading cause of blindness in working-age people. Usually, DR progresses from the asymptomatic non-proliferative DR that does not significantly alter vision, to proliferative DR (PDR), which can result in aberrant retinal neovessel formation and blindness. The High-Mobility-Group A1 (HMGA1) protein is a transcriptional master regulator of numerous genes, including metabolic and inflammatory genes, which, by modulating the expression of angiogenic factors, may induce retinal neovascularization, a hallmark of PDR. Herein, we examined the relationship between HMGA1 rs139876191 variant and DR. Results revealed that patients with type 2 diabetes, who were carriers of the HMGA1 rs139876191 variant had a significantly lower risk of developing PDR, compared to non-carrier diabetic patients. From a mechanistic point of view, our findings indicated that, by adversely affecting HMGA1 protein expression and function, the HMGA1 rs139876191 variant played a key role in this protective mechanism by downregulating the expression of vascular endothelial growth factor A (VEGFA), a major activator of neovascularization in DR. These data provide new insights into the pathogenesis and progression of DR, and may offer opportunities for discovering novel biomarkers and therapeutic targets for diagnosis, prevention and treatment of PDR.

SUBMITTER: Chiefari E

PROVIDER: S-EPMC5171873 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression.

Chiefari Eusebio E Ventura Valeria V Capula Carmelo C Randazzo Giorgio G Scorcia Vincenzo V Fedele Monica M Arcidiacono Biagio B Nevolo Maria Teresa MT Bilotta Francesco Luciano FL Vitiello Michela M Palmieri Camillo C Gulletta Elio E Fusco Alfredo A Foti Daniela D Vero Raffaella R Brunetti Antonio A

Scientific reports 20161219

Diabetic retinopathy (DR) is a major complication of diabetes mellitus, and is the leading cause of blindness in working-age people. Usually, DR progresses from the asymptomatic non-proliferative DR that does not significantly alter vision, to proliferative DR (PDR), which can result in aberrant retinal neovessel formation and blindness. The High-Mobility-Group A1 (HMGA1) protein is a transcriptional master regulator of numerous genes, including metabolic and inflammatory genes, which, by modula ...[more]

PMID: 27991577

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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.

Dataset Information

A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression.

Publications

A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression.

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