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.

Long-Term Effectiveness of Liraglutide for Weight Management and Glycemic Control in Type 2 Diabetes

“…Participants were recruited only from endocrinological outpatient clinics within the Catanzaro area, assuring simplified communication channels between practitioners and medical researchers, and small variability regarding data collection. Furthermore, we took advantage of the comparatively genetic homogeneity of the Calabrian population [43][44][45], which may allow for a small inter-individual variability in pharmacological responses [46,47]. Nonetheless, our results can only be applied to patients who show a positive response to Liraglutide and no safety concerns, which would otherwise prevent a 5-year prolonged therapy.…”

Angiopoietin-like 3 Is a Potential Biomarker for Retinopathy in Type 2 Diabetic Patients

“…We noted that very few population studies were performed to explore the biomarkers that are associated with DR severity. 17 Most of the studies recruited small numbers of NPDR and PDR patients (n ¼ 19-473) 5,[18][19][20] or exclusively PDR subjects (n ¼ 9-42). 4,[21][22][23][24] Although ANGPTL4 has been found increased in PDR patients, the number of patients ranged from 28 to 53.…”

Annexin A2 Promotes Development of Retinal Neovascularization through PI3K/ AKT Pathway

“…Therefore, the risk of intravitreal infection is much higher and some patients also respond poorly to anti-VEGF treatments [42] .Thus, identification of novel targets that play important roles in retinal neovascularization is urgently needed for those not responsible for anti-VEGF therapy [43] . Studies also demonstrated that celecoxib could inhibit the expression of VEGF and neovascularization growth in retinal pigment epithelial cells and the effect was mediated through a PI3K/AKT-dependent manner [44] and abrogating of VEGF significantly reduced the risk of developing to PDR in type 2 diabetes patients [45] .…”