Unraveling the role of genetics in the pathogenesis of diabetic retinopathy

Sharma, Ashok; Valle, María Luisa del; Beveridge, Connor; Liu, Yutao; Sharma, Shruti

doi:10.1038/s41433-019-0337-y

Cited by 32 publications

(20 citation statements)

References 67 publications

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“…Diabetic retinopathy (DR) is considered to be among the most severe causes of vision impairment and loss in the working-aged and elderly population [1], and the incidence of DR increases annually worldwide [2][3][4][5]. Due to the complex etiology of DR and other factors, the pathogenesis of DR is not entirely clear [6]. Therefore, continuing research is necessary to elucidate the pathogenesis and underlying molecular mechanisms of the development and progression of DR.…”

Section: Introductionmentioning

confidence: 99%

Transthyretin Upregulates Long Non-Coding RNA MEG3 by Affecting PABPC1 in Diabetic Retinopathy

Fan

Zhang

et al. 2019

IJMS

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The aim of the study was to demonstrate how transthyretin (TTR) could affect long non-coding RNA (lncRNA) of maternally expressed gene 3 (MEG3) and play important roles in diabetic retinopathy (DR). A DR model in C57BL/6 mice was established after intraperitoneal injection of streptozotocin (STZ). After intravitreal injection with TTR pAAV vector, MEG3 short hairpin RNA (shRNA), scrambled shRNA, or MEG3, retinal imaging, retinal trypsin digestion, and fundus vascular permeability tests were performed. Cell counting kit-8 (CCK8), transwell, and Matrigel assays were employed to detect the proliferation and migration of human retinal microvascular endothelial cells (hRECs). The binding between long non-coding RNA of maternally expressed gene 3 (lncRNA-MEG3) and microRNA-223-3p (miR-223-3p) was observed by using luciferase reporter assays, while co-immunoprecipitation (co-IP) was employed to confirm the interaction between TTR and the target. In the DR mice model, retinal vascular leakage and angiogenesis were repressed by overexpressing TTR. In vitro, the added TTR promoted the level of lncRNA-MEG3 by interacting with poly (A) binding protein cytoplasmic 1 (PABPC1), and then repressed proliferation and angiogenesis of hRECs. In vivo, silencing or overexpressing lncRNA-MEG3 significantly affected retinal vascular phenotypes. Additionally, the interaction between lncRNA-MEG3 and miR-223-3p was confirmed, and silencing of miR-223-3p revealed similar effects on hRECs as overexpression of lncRNA-MEG3. In summary, in the DR environment, TTR might affect the lncRNA MEG3/miR-223-3p axis by the direct binding with PABPC1, and finally repress retinal vessel proliferation.Keywords: diabetic retinopathy (DR); transthyretin (TTR); long non-coding RNA (lncRNA); maternally expressed gene 3 (MEG3); polyadenylate-binding protein cytoplasmic 1 (PABPC1) Int.In the eyes, transthyretin (TTR) is mainly expressed in human retinal pigment epithelial cells (hRPECs) and the choroid [7], and it usually works as the carrier of thyroxine (T4) and retinol [8,9]. As previously reported, TTR should be correlated with diabetes-associated diseases, e.g., type I diabetes patients showed lower serum TTR levels [10]. In clinical investigations, myopia was revealed to protect diabetic patients from suffering DR [11,12]. Our previous work has demonstrated that higher vitreous TTR content of high myopia patient [13] might help to prevent the progression of DR [14]. The serum and vitreous TTR levels in DR patients were associated with DR progression [15]; TTR suppressed angiogenesis by affecting the angiopoietin-Tie signaling pathway in hyperglycemia [16], and enhanced the apoptosis of hRECs through a hypoxia-associated 78-kDa glucose-regulated protein (GRP78)-dependent pathway [17]. Still, the regulatory mechanisms involving TTR in DR are not entirely clear.Long non-coding RNAs (lncRNAs) regulate targeted mRNA expression via the microRNA (miRNA) response element known as competing endogenous RNA (ceRNA) [18,19]. LncRNAs are known to play vital roles in oc...

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Section: Introductionmentioning

confidence: 99%

Transthyretin Upregulates Long Non-Coding RNA MEG3 by Affecting PABPC1 in Diabetic Retinopathy

Fan

Zhang

et al. 2019

IJMS

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“…Additional polymorphisms reported to be significantly associated with DR included NOS3, VEGFA, integrin subunit alpha 2 (ITGA2), and intercellular adhesion molecule 1(ICAM1) [26]. More recently, Sharma et al (2019) elegantly summarized candidate gene studies associated with DR in a review highlighting 65 different genes [27]. These candidate genes are involved in a variety of cellular processes, such as glucose metabolism, inflammation, angiogenesis, and neurogenesis.…”

Section: Genetic Studies 41 Candidate Gene Studiesmentioning

confidence: 99%

Genetics of Diabetic Retinopathy, a Leading Cause of Irreversible Blindness in the Industrialized World

Bhatwadekar

Shughoury

Belamkar

et al. 2021

Genes

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Diabetic retinopathy (DR) is a chronic complication of diabetes and a leading cause of blindness in the industrialized world. Traditional risk factors, such as glycemic control and duration of diabetes, are unable to explain why some individuals remain protected while others progress to a more severe form of the disease. Differences are also observed in DR heritability as well as the response to anti-vascular endothelial growth factor (VEGF) treatment. This review discusses various aspects of genetics in DR to shed light on DR pathogenesis and treatment. First, we discuss the global burden of DR followed by a discussion on disease pathogenesis as well as the role genetics plays in the prevalence and progression of DR. Subsequently, we provide a review of studies related to DR’s genetic contribution, such as candidate gene studies, linkage studies, and genome-wide association studies (GWAS) as well as other clinical and meta-analysis studies that have identified putative candidate genes. With the advent of newer cutting-edge technologies, identifying the genetic components in DR has played an important role in understanding DR incidence, progression, and response to treatment, thereby developing newer therapeutic targets and therapies.

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“…One example is the aforementioned JAK-STAT pathway affected in DKD. As the JAK-STAT pathway is also affected in DRD [ 107 ], it is possible that baricitinib [ 77 ], or other ocular therapeutics that act on this JAK-STAT pathway may become viable treatment options for DRD. If useful in DRD treatment, baricitinib would continue the history of discovering effective DRD therapies from clinical trials focused outside of the eye.…”

Section: Shared Pathophysiology Of Drd and Dkd: An Avenue For Furtmentioning

confidence: 99%

Integrative Biology of Diabetic Retinal Disease: Lessons from Diabetic Kidney Disease

Pan

Gardner

Harder

2021

JCM

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Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research techniques, including animal and tissue culture models—a problem shared by those in the field of kidney disease research. By contrast, significant progress in the study of diabetic kidney disease (DKD) has resulted from the successful employment of systems biology approaches. Systems biology is widely used to comprehensively understand complex human diseases through the unbiased integration of genetic, environmental, and phenotypic aspects of the disease with the functional and structural manifestations of the disease. The application of a systems biology approach to DRD may help to clarify the molecular basis of the disease and its progression. Acquiring this type of information might enable the development of personalized treatment approaches, with the goal of discovering new therapies targeted to an individual’s specific DRD pathophysiology and phenotype. Furthermore, recent efforts have revealed shared and distinct pathways and molecular targets of DRD and DKD, highlighting the complex pathophysiology of these diseases and raising the possibility of therapeutics beneficial to both organs. The objective of this review is to survey the current understanding of DRD pathophysiology and to demonstrate the investigative approaches currently applied to DKD that could promote a more thorough understanding of the structure, function, and progression of DRD.

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Unraveling the role of genetics in the pathogenesis of diabetic retinopathy

Cited by 32 publications

References 67 publications

Transthyretin Upregulates Long Non-Coding RNA MEG3 by Affecting PABPC1 in Diabetic Retinopathy

Transthyretin Upregulates Long Non-Coding RNA MEG3 by Affecting PABPC1 in Diabetic Retinopathy

Genetics of Diabetic Retinopathy, a Leading Cause of Irreversible Blindness in the Industrialized World

Integrative Biology of Diabetic Retinal Disease: Lessons from Diabetic Kidney Disease

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