scholarly journals Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1379
Author(s):  
Dongjoon Kim ◽  
Hiromi Sesaki ◽  
Sayon Roy
Keyword(s):  
Diabetic Retinopathy ◽  
Cell Loss ◽  
Vascular Lesions ◽  
Protective Effects ◽  
Diabetic Mice ◽  
Wild Type ◽  
Apoptotic Genes ◽  
Retinal Vascular Lesions ◽  
Acellular Capillaries ◽  
Pericyte Loss

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

scholarly journals Opa1 Deficiency Promotes Development of Retinal Vascular Lesions in Diabetic Retinopathy

2021 ◽  
Vol 22 (11) ◽  
pp. 5928
Author(s):  
Dongjoon Kim ◽  
Marcela Votruba ◽  
Sayon Roy
Keyword(s):  
Diabetic Retinopathy ◽  
Caspase 3 ◽  
Vascular Lesions ◽  
Apoptotic Cells ◽  
Diabetic Mice ◽  
Cytochrome C Release ◽  
Retinal Vascular Lesions ◽  
Acellular Capillaries ◽  
Pericyte Loss ◽  
Retinal Capillaries

This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/− mice, and diabetic Opa1+/− mice were used in this study. 16 weeks after diabetes onset, retinas were assessed for Opa1 and Bax levels by Western blot analysis, and retinal networks were examined for acellular capillaries (AC) and pericyte loss (PL). Apoptotic cells were detected in retinal capillaries using TUNEL assay, and caspase-3 activity was assessed using fluorometric analysis. Opa1 expression was significantly downregulated in retinas of diabetic and Opa1+/− mice compared with those of WT mice. Inducing diabetes further decreased Opa1 expression in retinas of Opa1+/− mice. Increased cytochrome c release concomitant with increased level of pro-apoptotic Bax and elevated caspase-3 activity were observed in retinas of diabetic and Opa1+/− mice; the number of TUNEL-positive cells and AC/PL was also significantly increased. An additional decrease in the Opa1 level in retinas of diabetic Opa1+/− mice exacerbated the development of apoptotic cells and AC/PL compared with those of diabetic mice. Diabetes-induced Opa1 downregulation contributes, at least in part, to the development of retinal vascular lesions characteristic of DR.

scholarly journals Effects of Diabetes on Microcirculation and Leukostasis in Retinal and Non-Ocular Tissues: Implications for Diabetic Retinopathy

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1583
Author(s):  
Ana Silva Herdade ◽  
Iara Mota Silva ◽  
Ângelo Calado ◽  
Carlota Saldanha ◽  
Ngan-Ha Nguyen ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Diabetic Control ◽  
Vascular Lesion ◽  
Vascular Lesions ◽  
Diabetic Mice ◽  
Capillary Networks ◽  
Retinal Microcirculation ◽  
Retinal Vascular Lesions ◽  
Acellular Capillaries ◽  
Pericyte Loss

Changes in retinal microcirculation are associated with the development of diabetic retinopathy (DR). However, it is unclear whether such changes also develop in capillary beds of other non-retinal tissues. Here, we investigated microcirculatory changes involving velocity of rolling neutrophils, adherence of neutrophils, and leukostasis during development of retinal vascular lesions in diabetes in other non-retinal tissues. Intravital microscopy was performed on post-capillary venules of cremaster muscle and ear lobe of mice with severe or moderate diabetes and compared to those of non-diabetic mice. Additionally, number and velocity of rolling leukocytes, number of adherent leukocytes, and areas of leukostasis were quantified, and retinal capillary networks were examined for acellular capillaries (AC) and pericyte loss (PL), two prominent vascular lesions characteristic of DR. The number of adherent neutrophils and areas of leukostasis in the cremaster and ear lobe post-capillary venules of diabetic mice was increased compared to those of non-diabetic mice. Similarly, a significant increase in the number of rolling neutrophils and decrease in their rolling velocities compared to those of non-diabetic control mice were observed and severity of diabetes exacerbated these changes. Understanding diabetes-induced microcirculatory changes in cremaster and ear lobe may provide insight into retinal vascular lesion development in DR.

scholarly journals Crocin Improves Insulin Sensitivity and Ameliorates Adiposity by Regulating AMPK-CDK5-PPARγ Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Kai Fang ◽  
Ming Gu
Keyword(s):  
Protein Level ◽  
Biological Activities ◽  
Protective Effects ◽  
Metabolic Dysfunction ◽  
Ampk Activation ◽  
Diabetic Mice ◽  
Wild Type ◽  
Ampk Signaling ◽  
Beneficial Effects

Crocin is a carotenoid compound which possesses multiple biological activities. Our and other laboratory’s previous findings show that crocin alleviates obesity and type 2 diabetes-related complications. We have found that crocin activates AMP-activated protein kinase (AMPK) signaling and inhibition of AMPK suppresses crocin-induced protective effects. However, the causal role of AMPK activation in the biological role of crocin is still not verified. In the present study, we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice. In AMPKα KO diabetic mice, those protective effects of crocin against glucose and lipid metabolic dysfunction were abolished. These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction. Moreover, we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPKα. We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice, while this effect was abolished in AMPKα KO diabetic mice. The regulation of downstream targets of CDK5/PPARγ by crocin was abolished by the deficiency of AMPK. In conclusion, our study verified that activation of AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction. Activation of AMPK downregulates the protein level of CDK5, followed by the decrease of PPARγ phosphorylation, leading to the inhibition of adipose formation and metabolic dysfunction. Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARγ signaling.

scholarly journals mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

2020 ◽  
Author(s):  
Sanjar Batirovich Madrakhimov ◽  
Jin Young Yang ◽  
Jin Ha Kim ◽  
Jung Woo Han ◽  
Tae Kwann Park
Keyword(s):  
Diabetic Retinopathy ◽  
Ganglion Cell ◽  
Ganglion Cells ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Diabetic Mice ◽  
Tissue Samples ◽  
Glucose Transporter 1 ◽  
Apoptosis Pathway

Abstract Background: Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in diabetic retinopathy. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of diabetic retinopathy was investigated in 1-month-diabetic mice treated with phlorizin or rapamycin. The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin or MHY1485. Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis.Results: mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker – cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer (GCL), as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion: Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

scholarly journals Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels

2020 ◽  
Author(s):  
Ada Admin ◽  
Francesco Tecilazich ◽  
Toan A. Phan ◽  
Fabio Simeoni ◽  
Giulia Maria Scotti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetic Retinopathy ◽  
General Circulation ◽  
Absolute Number ◽  
Retinal Vessels ◽  
Wild Type ◽  
Long Latency ◽  
History Of ◽  
Acellular Capillaries ◽  
Patrolling Monocytes

In diabetes there is a long latency between onset of hyperglycemia and appearance of structural microangiopathy. Because Ly6C<sup>low</sup> patrolling monocytes (PMo) behave as housekeepers of the vasculature, we tested whether PMo protect microvessels against diabetes. <p>We found that, in wild-type mice,<b> </b>diabetes reduced PMo in the general circulation but increased by 4-fold the absolute number of PMo adherent to retinal vessels (leukostasis). Conversely, in diabetic NR4A1<sup>-/-</sup> mice ─ a model of absence of PMo ─ there was no increase in leukostasis at all; and at 6 months of diabetes the number of retinal acellular capillaries almost doubled when compared to diabetic wild-type mice. Circulating PMo showed gene expression changes indicative of enhanced migratory, vasculo-protective, and housekeeping activities; as well as profound suppression of genes related to inflammation and apoptosis. Pro-migratory CXCR4 was no longer upregulated at longer duration, when retinal acellular capillaries begin to increase.</p> <p>Thus, after short diabetes duration, PMo are the cells preferentially recruited to the retinal vessels and protect vessels from diabetic damage. These observations support the need for reinterpretation of the functional meaning of leukostasis in diabetes, and document within the natural history of diabetic retinopathy processes of protection-repair that can provide novel paradigms for prevention. </p>

scholarly journals Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7

2019 ◽  
Vol 20 (9) ◽  
pp. 2101 ◽  
Author(s):  
Sofia Pavlou ◽  
Josy Augustine ◽  
Rónán Cunning ◽  
Kevin Harkin ◽  
Alan W. Stitt ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Therapeutic Potential ◽  
Neuronal Degeneration ◽  
Amacrine Cells ◽  
Oscillatory Potentials ◽  
Transcriptase Inhibitor ◽  
Vascular Pathology ◽  
Vascular Lesions ◽  
Diabetic Mice ◽  
New Treatments

Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes.

Patrolling monocytes are recruited and activated by diabetes to protect retinal microvessels

2020 ◽  
Author(s):  
Ada Admin ◽  
Francesco Tecilazich ◽  
Toan A. Phan ◽  
Fabio Simeoni ◽  
Giulia Maria Scotti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetic Retinopathy ◽  
General Circulation ◽  
Absolute Number ◽  
Retinal Vessels ◽  
Wild Type ◽  
Long Latency ◽  
History Of ◽  
Acellular Capillaries ◽  
Patrolling Monocytes

In diabetes there is a long latency between onset of hyperglycemia and appearance of structural microangiopathy. Because Ly6C<sup>low</sup> patrolling monocytes (PMo) behave as housekeepers of the vasculature, we tested whether PMo protect microvessels against diabetes. <p>We found that, in wild-type mice,<b> </b>diabetes reduced PMo in the general circulation but increased by 4-fold the absolute number of PMo adherent to retinal vessels (leukostasis). Conversely, in diabetic NR4A1<sup>-/-</sup> mice ─ a model of absence of PMo ─ there was no increase in leukostasis at all; and at 6 months of diabetes the number of retinal acellular capillaries almost doubled when compared to diabetic wild-type mice. Circulating PMo showed gene expression changes indicative of enhanced migratory, vasculo-protective, and housekeeping activities; as well as profound suppression of genes related to inflammation and apoptosis. Pro-migratory CXCR4 was no longer upregulated at longer duration, when retinal acellular capillaries begin to increase.</p> <p>Thus, after short diabetes duration, PMo are the cells preferentially recruited to the retinal vessels and protect vessels from diabetic damage. These observations support the need for reinterpretation of the functional meaning of leukostasis in diabetes, and document within the natural history of diabetic retinopathy processes of protection-repair that can provide novel paradigms for prevention. </p>

Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss

2006 ◽  
Vol 95 (04) ◽  
pp. 689-695 ◽  
Author(s):  
Jennifer Hoffmann ◽  
Alex Alt ◽  
Jihong Lin ◽  
Günther Lochnit ◽  
Uwe Schubert ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Endothelial Cell ◽  
Vegf Expression ◽  
Endothelial Proliferation ◽  
High Doses ◽  
Acellular Capillaries ◽  
Pericyte Loss ◽  
The Impact

SummaryHyperglycemia-induced mitochondrial overproduction of reactive oxygen species leads to the activation of different biochemical pathways involved in endothelial damage of the diabetic retina. Tenilsetam [(±)-3-(2-thienyl)-2-piperazinone] is a dicarbonyl scavenger in the millimolar range anda transition metal ion chelator in the micromolar range. We tested its effect on experimental diabetic retinopathy, and on endothelial cell characteristics in vitro. Streptozotocin diabetic male Wistar rats (60 mg/ kg BW) received 50 mg/kg BW tenilsetam (D-T) for 36 weeks, or no treatment (D).The impact of tenilsetam (0–30 mM) on endothelial proliferation, apoptosis, sprouting, cytokine-induced leucocyte-endothelial interaction, and VEGF expression was tested in vitro.Tenilsetam did not affect glycemic control or body weight in diabetic animals. The 3.7 fold increase in acellular capillaries in diabetic rats [p<0.001 vs. non-diabetic controls (N)] was reduced by 70% (p<0.001) through treatment, but pericyte loss (D vs. N –33%; p<0.001) remained unaffected. In vitro, tenilsetam inhibited endothelial proliferation at lower doses, while inducing apoptosis at high doses. Leucocyte adhesion was only inhibited at high doses. Sprouting angiogenesis of bovine retinal endothelial cells was promoted at lower doses (≤ 10 mM). At micromolar concentrations, endothelial VEGF expression was upregulated by 100%. Long-term treatment with the AGEinhibitor and iron-chelating compound tenilsetam inhibits the formation of acellular capillaries without correcting pericyte loss. The compound has dose-dependent effects on endothelial cell function. These data suggest that, independent of known properties, tenilsetam shows important rescue functions on endothelial cells which could be useful for the treatment of early diabetic retinopathy.

scholarly journals Susceptibility of Diabetic Mice to Noise Trauma

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Wook Kyoung Han ◽  
Eung Hyub Kim ◽  
Sun-Ae Shin ◽  
Dong-Sik Shin ◽  
Bong Jik Kim ◽  
...  
Keyword(s):  
Noise Exposure ◽  
Inflammatory Responses ◽  
Hearing Threshold ◽  
Cell Loss ◽  
Oxygen Species ◽  
Diabetic Mice ◽  
Hair Cell Loss ◽  
Wild Type ◽  
Noise Trauma ◽  
Species Production

Diabetes can lead to many end-organ complications. However, the association between diabetes and hearing loss is not well understood. Here, we investigated the effect of noise exposure on diabetic mice compared with wild-type mice. Hearing threshold shifts, histopathologic changes in the cochlea, and inflammatory responses were evaluated over time. After noise exposure, more severe hearing threshold shifts, auditory hair cell loss, and synaptopathies were notable in diabetic mice compared with wild-type mice. Moreover, increased inflammatory responses and reactive oxygen species production were observed in the ears of diabetic mice. The results demonstrated that diabetic mice are more susceptible to noise trauma.

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