Pathogenetic Mechanisms in Diabetic Retinopathy: From Molecules to Cells to Tissues

Biswas, Saumik; Chakrabarti, Subrata

doi:10.1007/978-3-319-60324-7_9

Cited by 6 publications

(15 citation statements)

References 253 publications

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“…Hyperglycaemia is the central event leading to micro-and macrovascular pathologies in diabetes [44]. Endothelial cells are exposed to circulating blood glucose and are the primary cell type to be affected by hyperglycaemia [44][45][46]. Endothelial cell dysfunction ensues as endothelial cells lose their quiescence, elude their normal function and acquire new phenotypes [32,45].…”

Section: Discussionmentioning

confidence: 99%

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

et al. 2019

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Aims/hypothesis The pathophysiology of diabetic retinopathy is linked to hyperglycaemia and its effect on retinal microvascular tissues. The resulting endothelial injury changes the endothelial cell phenotype to acquire mesenchymal properties (i.e. endothelial-mesenchymal transition [EndMT]). Such changes can be regulated by epigenetic mechanisms, including long non-coding RNAs (lncRNAs). lncRNA H19 may influence EndMT through TGF-β. We investigated the role of H19 in regulating EndMT during diabetic retinopathy. Methods H19 was overexpressed or silenced in human retinal endothelial cells exposed to various glucose levels. The cells were examined for H19, endothelial and mesenchymal markers. We then expanded the study to retinal tissues in a mouse model of diabetic retinopathy and also examined vitreous humour samples from individuals with proliferative diabetic retinopathy. Results Expression of H19 was downregulated in high glucose conditions (25 mmol/l). H19 overexpression prevented glucoseinduced EndMT. Such changes appear to involve TGF-β through a Smad-independent mechanism. Diabetes caused downregulation of retinal H19. Using H19 knockout mice, we demonstrated similar EndMT in the retina. Examination of vitreous humour from individuals with proliferative diabetic retinopathy also reinforced the downregulation of H19 in diabetes. Conclusions/interpretationWe therefore concluded that H19 regulates EndMT in diabetic retinopathy through specific mechanisms. Data availability The results from our previous microarray can be found online using the GEO accession number GSE122189.

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Section: Discussionmentioning

confidence: 99%

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

et al. 2019

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“…Hyperglycemia in DM alters biochemical and metabolic pathways, contributing to vascular damage in chronic complications. 2 In this study, we investigated diabetic retinopathy (DR), which is a debilitating microvascular complication and a major cause of blindness worldwide. 3 DR can be categorized as non-proliferative DR and proliferative DR (PDR), the latter manifesting as pathological neovascularization.…”

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confidence: 99%

“…3 DR can be categorized as non-proliferative DR and proliferative DR (PDR), the latter manifesting as pathological neovascularization. [1][2][3] In PDR, angiogenesis occurs due to the activation of various signaling cascades that promote increased levels of angiogenic factors. 4 These factors mediate the proliferation of retinal endothelial cells (ECs), leading to abnormal neovascularisation.…”

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confidence: 99%

“…3 Vascular endothelial growth factor (VEGF) is a potent angiogenic factor expressed by ECs and non-ECs, and several pathological processes, including hypoxia, 5 oxidative stress, 6 and inflammation, 7 stimulate VEGF expression through transcriptional regulation, including non-coding RNAs. 2,8,9 Due to the critical role of VEGF, the first-line therapy for patients with diabetic macular edema (DME) and PDR consists of intravitreal injections of anti-VEGF. However, such therapies have limitations where frequent intraocular injections are required and have local or systemic adverse effects.…”

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confidence: 99%

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The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

Biswas

Feng

Chen

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Diabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the epigenetic implications of HOTAIR in DR, and we investigated such relationships herein. METHODS.We used HRECs exposed to various glucose concentrations and epigenetic modulators to examine HOTAIR, angiogenic, and DR-related molecular markers. Oxidative stress, angiogenesis, and mitochondrial dysfunction were assessed. Retinal tissues of diabetic rodents and the vitreous humor and serum of patients with proliferative DR were also investigated. RESULTS.Hyperglycemia significantly augmented HOTAIR expression in HRECs and promoted angiogenesis, oxidative damage, and mitochondrial aberrations. Similarly, vitreous humor and serum from proliferative DR patients and retinas from diabetic animals demonstrated increased HOTAIR expression compared to non-diabetic controls. HOTAIR knockdown protected against glucose-induced increases of angiogenic and diabetesassociated molecules in the retina. Mechanistically, we showed that HOTAIR exerts its capabilities by preventing oxidative stress and modulating epigenetic pathways involving histone methylation, histone acetylation, DNA methylation, and transcription factors. CONCLUSIONS.Our findings suggest that HOTAIR is a critical lncRNA in the pathogenesis of DR and may potentially be important for diagnostic and therapeutic targeting.

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“…Inflammation is a key participant in the pathogenesis of diabetes and its complications (44). During inflammatory processes, TNF-α and IL-6 are upregulated (26-28, 34, 39, 45).…”

Section: Discussionmentioning

confidence: 99%

Curcumin Analogs Reduce Stress and Inflammation Indices in Experimental Models of Diabetes

et al. 2019

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Chronic inflammation and oxidative stress lead to a multitude of adverse cellular responses in target organs of chronic diabetic complications. Curcumin, a highly investigated phytochemical, has been shown to exhibit both anti-inflammatory and antioxidant activities. However, the clinical application of curcumin has been greatly limited due to a poor pharmacokinetic profile. To overcome these limitations, we have generated analogs of curcumin to enhance bioavailability and offer a preferable pharmacokinetic profile. Here, we explored the effects of two mono-carbonyl curcumin analogs, L2H21 and L50H46, in alleviating indices of inflammation and oxidative stress in cell culture and mouse model of diabetic complications. Our results show that L2H21 and L50H46 normalize inflammatory mediators (IL-6 and TNF-α), extracellular matrix proteins (FN and COL4α1), vasoactive factors (VEGF and ET-1) and a key transcriptional coactivator (p300) in cultured human retinal microvascular endothelial cells (HRECs) and dermal-derived microvascular endothelial cells (HMVECs) challenged with high levels of glucose. These curcumin analogs also reduced glucose-induced oxidative DNA damage as evidenced by 8-OHdG labeling. We further show that treatment of streptozotocin-induced diabetic mice with curcumin analogs prevents cardiac and renal dysfunction. The preservation of target tissue function was associated with normalization of pro-inflammatory cytokines and matrix proteins. Collectively, our results show that L2H21 and L50H46 offer the anti-inflammatory and antioxidant activities as has been reported for curcumin, and may provide a clinically applicable therapeutic option for the treatment of diabetic complications.

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Pathogenetic Mechanisms in Diabetic Retinopathy: From Molecules to Cells to Tissues

Cited by 6 publications

References 253 publications

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

lncRNA H19 prevents endothelial–mesenchymal transition in diabetic retinopathy

The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

Curcumin Analogs Reduce Stress and Inflammation Indices in Experimental Models of Diabetes

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