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 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 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 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.

scholarly journals Rhein ElicitsIn VitroCytotoxicity in Primary Human Liver HL-7702 Cells by Inducing Apoptosis through Mitochondria-Mediated Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Guy-Armel Bounda ◽  
Wang Zhou ◽  
Dan-dan Wang ◽  
Feng Yu
Keyword(s):  
Cytochrome C ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Fatty Degeneration ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Induced Apoptosis

Objective. To study rhein-induced apoptosis signaling pathway and to investigate its molecular mechanisms in primary human hepatic cells.Results. Cell viability of HL-7702 cells treated with rhein showed significant decrease in dose-dependent manner. Following rhein treatment (25 μM, 50 μM, and 100 μM) for 12 h, the detection of apoptotic cells was significantly analyzed by flow cytometry and nuclear morphological changes by Hoechst 33258, respectively. Fatty degeneration studies showed upregulation level of the relevant hepatic markers (P< 0.01). Caspase activities expressed significant upregulation of caspase-3, caspase-9, and caspase-8. Moreover, apoptotic cells by rhein were significantly inhibited by Z-LEHD-FMK and Z-DEVD-FMK, caspase-9 inhibitor, and caspase-3 inhibitor, respectively. Overproduction of reactive oxygen species, lipid peroxidation, and loss of mitochondrial membrane potential were detected by fluorometry. Additionally, NAC, a ROS scavenger, significantly attenuated rhein-induced oxidative damage in HL-7702 cells. Furthermore, real-time qPCR results showed significant upregulation of p53, PUMA, Apaf-1, and Casp-9 and Casp-3 mRNA, with no significant changes of Fas and Cytochrome-c. Immunoblotting revealed significant Cytochrome-c release from mitochondria into cytosol and no change in Fas expression.Conclusion. Taken together, these observations suggested that rhein could induce apoptosis in HL-7702 cells via mitochondria-mediated signal pathway with involvement of oxidative stress mechanism.

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 Metabolic Memory Phenomenon and Accumulation of Peroxynitrite in Retinal Capillaries

2007 ◽  
Vol 2007 ◽  
pp. 1-7 ◽  
Author(s):  
Renu A. Kowluru ◽  
Mamta Kanwar ◽  
Alexander Kennedy
Keyword(s):  
Diabetic Retinopathy ◽  
Glycemic Control ◽  
Antioxidant Capacity ◽  
Total Antioxidant Capacity ◽  
Metabolic Memory ◽  
Retinal Microvasculature ◽  
Total Antioxidant ◽  
Acellular Capillaries ◽  
Mnsod Activity ◽  
Retinal Capillaries

Aim. Diabetic retinopathy resists reversal after good glycemic control (GC) is reinitiated, and preexisting damage at the time of intervention is considered as the major factor in determining the outcome of the GC. This study is to investigate the role of peroxynitrite accumulation in the retinal capillaries in the failure of retinopathy to reverse after reestablishment of GC, and to determine the effect of this reversal on the activity of the enzyme responsible for scavenging mitochondrial superoxide, MnSOD.Methods. In streptozotocin-diabetic rats, 6 months of poor glycemic control (PC, glycated hemoglobin,GHb>12.0%) was followed by 6 additional months of GC (GHb about 6%). The trypsin-digested retinal microvessels were prepared for immunostaining of nitrotyrosine (a measure of peroxynitrite) and for counting the number of acellular capillaries (a measure of histopathology). The retina from the other eye was used to quantify nitrotyrosine concentration, MnSOD activity and the total antioxidant capacity.Results. Reversal of hyperglycemia after 6 months of PC had no significant effect on nitrotyrosine concentration in the retina, on the nitrotyrosine-positive retinal capillary cells and on the number of acellular capillaries; the values were similar in PC-GC and PC groups. In the same rats retinal MnSOD activity remained inhibited and the total antioxidant capacity was subnormal 6 months after cessation of PC.Conclusions. Peroxynitrite accumulation in the retinal microvasculature, the site of histopathology, fails to normalize after reversal of hyperglycemia, and superoxide remains inadequately scavenged. This failure of reversal of peroxynitrite accumulation could be, in part, responsible for the resistance of diabetic retinopathy to reverse after termination of PC.

scholarly journals Pericyte Bridges in Homeostasis and Hyperglycemia: Reconsidering Pericyte Dropout and Microvascular Structures

2019 ◽  
Author(s):  
Bruce A. Corliss ◽  
H. Clifton Ray ◽  
Richard Doty ◽  
Corbin Mathews ◽  
Natasha Sheybani ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Basement Membrane ◽  
In Vivo Imaging ◽  
Diabetic Patients ◽  
Cell Type ◽  
A Cell ◽  
Acellular Capillaries ◽  
Pericyte Loss

AbstractDiabetic retinopathy threatens the vision of a third of diabetic patients. Progression of the disease is attributed to the dropout of pericytes, a cell type that enwraps and stabilizes the microvasculature. In tandem with this presumptive pericyte dropout, there is enriched formation of structures assumed to be remnants of collapsed or regressed vessels, previously classified as acellular capillaries, string vessels, and basement membrane bridges. Instead of endothelial cells, we show that pericytes colocalize with basement membrane bridges, and both bridging structures are enriched by cell-specific knockout of KLF4 and reversibly enriched with elevation of Ang-2, PDGF-BB, and blood sugar. Our data suggests that pericyte counts from retinal digests have misclassified pericyte bridges as endothelial structures and have exaggerated the role of pericyte loss in DR progression. In vivo imaging of corneal limbal vessels demonstrates pericyte migration off-vessel, implicating pericyte movement in formation of pericyte bridges and pathogenesis of diabetic retinopathy.

Association of reduced Connexin 43 expression with retinal vascular lesions in human diabetic retinopathy

2016 ◽  
Vol 146 ◽  
pp. 103-106 ◽  
Author(s):  
Thomas Tien ◽  
Tetsuya Muto ◽  
Joyce Zhang ◽  
Elliott H. Sohn ◽  
Robert F. Mullins ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Connexin 43 ◽  
Vascular Lesions ◽  
Retinal Vascular Lesions
Sign in / Sign up

Export Citation Format

Share Document