Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes

Purpose: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse model of early diabetic retinopathy (DR). Methods: Adult C57BL/6J mice were treated with streptozotocin (STZ) and made diabetic at 8–10 weeks of age. Control and diabetic mice were treated with vehicle or TUDCA starting 1 or 3 weeks after induction of diabetes, and were assessed bimonthly for visual function via an optomotor response and monthly for retinal function via scotopic electroretinograms. Results: Diabetic mice showed significantly reduced spatial frequency and contrast sensitivity thresholds compared to control mice, while diabetic mice treated early with TUDCA showed preservation at all timepoints. A-wave, b-wave, and oscillatory potential 2 (OP2) amplitudes decreased in diabetic mice. Diabetic mice also exhibited delays in a-wave and OP2-implicit times. Early TUDCA treatment ameliorated a-wave, b-wave, and OP2 deficits. Late TUDCA treatment showed reduced preservation effects compared to early treatment. Conclusions: Early TUDCA treatment preserved visual function in an STZ-mouse model of Type I diabetes. These data add to a growing body of preclinical research that may support testing whether TUDCA may be an effective early clinical intervention against declining visual function caused by diabetic retinopathy.

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Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice.

International Immunology ◽

10.1093/intimm/10.12.1765 ◽

1998 ◽

Vol 10 (12) ◽

pp. 1765-1776 ◽

Cited By ~ 30

Author(s):

R. J. Boyton ◽

T. Lohmann ◽

M. Londei ◽

H. Kalbacher ◽

T. Halder ◽

...

Keyword(s):

Transgenic Mice ◽

Glutamic Acid ◽

T Lymphocyte ◽

Glutamic Acid Decarboxylase ◽

Type I Diabetes ◽

Acid Decarboxylase ◽

Type I ◽

Diabetic Mice ◽

Hla Dq ◽

Lymphocyte Responses

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Ingested interferon α suppresses Type I diabetes in non-obese diabetic mice

Diabetologia ◽

10.1007/s001250051056 ◽

1998 ◽

Vol 41 (10) ◽

pp. 1227-1232 ◽

Cited By ~ 35

Author(s):

S. A. Brod ◽

M. Malone ◽

S. Darcan ◽

M. Papolla ◽

L. Nelson

Keyword(s):

Type I Diabetes ◽

Interferon Α ◽

Type I ◽

Diabetic Mice

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Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model

Cardiovascular Diabetology ◽

10.1186/1475-2840-9-55 ◽

2010 ◽

Vol 9 (1) ◽

pp. 55 ◽

Cited By ~ 9

Author(s):

Peter E Westerweel ◽

Cindy TJ van Velthoven ◽

Tri Q Nguyen ◽

Krista den Ouden ◽

Dominique PV de Kleijn ◽

...

Keyword(s):

Smooth Muscle ◽

Mouse Model ◽

Progenitor Cells ◽

Type I Diabetes ◽

Type I ◽

Muscle Progenitor Cells ◽

Diabetes Mouse

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Specific PKC βII inhibitor: one stone two birds in the treatment of diabetic foot ulcers

Bioscience Reports ◽

10.1042/bsr20171459 ◽

2018 ◽

Vol 38 (5) ◽

Cited By ~ 3

Author(s):

Sushant Kumar Das ◽

Yi Feng Yuan ◽

Mao Quan Li

Keyword(s):

Wound Healing ◽

Protein Kinase ◽

Peripheral Blood ◽

Wound Closure ◽

Type I Diabetes ◽

Healing Process ◽

Wound Healing Process ◽

Peripheral Blood Flow ◽

Type I ◽

Diabetic Mice

To explore whether or not inhibition of protein kinase C βII (PKC βII) stimulates angiogenesis as well as prevents excessive NETosis in diabetics thus accelerating wound healing. Streptozotocin (STZ, 60 mg/kg/day for 5 days, i.p.) was injected to induce type I diabetes in male ICR mice. Mice were treated with ruboxistaurin (30 mg/kg/day, orally) for 14 consecutive days. Wound closure was evaluated by wound area and number of CD31-stained capillaries. Peripheral blood flow cytometry was done to evaluate number of circulating endothelial progenitor cells (EPCs). NETosis assay and wound tissue immunofluorescence imaging were done to evaluate the percentage of neutrophils undergoing NETosis. Furthermore, the expression of PKC βII, protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and histone citrullation (H3Cit) were determined in the wound by Western blot analysis. Ruboxistaurin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in ruboxistaurin-treated diabetic mice. Moreover, ruboxistaurin treatment significantly decreases the percentages of H3Cit+ cells in both peripheral blood and wound areas. This prevented excess activated neutrophils forming an extracellular trap (NETs) formation. The expressions of phospho-Akt (p-Akt), phospho-eNOS (p-eNOS), and VEGF increased significantly in diabetic mice on ruboxistaurin treatment. The expressions of PKC βII and H3Cit+, on the other hand, decreased with ruboxistaurin treatment. The results of the present study suggest that ruboxistaurin by inhibiting PKC βII activation, reverses EPCs dysfunction as well as prevents exaggerated NETs formation in a diabetic mouse model; thereby accelerating the wound healing process.

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Genetic Markers in Early Diabetic Retinopathy of Adolescents With Type I Diabetes

Journal of Diabetes and its Complications ◽

10.1016/s1056-8727(96)00051-7 ◽

1997 ◽

Vol 11 (4) ◽

pp. 203-207 ◽

Cited By ~ 17

Author(s):

Aura A.K. Falck ◽

J.Mikael Knip ◽

Jorma S. Ilonen ◽

Leila T. Laatikainen

Keyword(s):

Diabetic Retinopathy ◽

Genetic Markers ◽

Type I Diabetes ◽

Type I

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Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

Frontiers in Pharmacology ◽

10.3389/fphar.2021.732630 ◽

2021 ◽

Vol 12 ◽

Author(s):

Scott J. Howell ◽

Chieh A. Lee ◽

Julia C. Batoki ◽

Thomas E. Zapadka ◽

Sarah I. Lindstrom ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Retinopathy ◽

New Drugs ◽

Type I ◽

Type Ii ◽

Diabetic Mice ◽

Junction Protein ◽

Type Ii Diabetics ◽

Retinal Inflammation

The global number of diabetics continues to rise annually. As diabetes progresses, almost all of Type I and more than half of Type II diabetics develop diabetic retinopathy. Diabetic retinopathy is a microvascular disease of the retina, and is the leading cause of blindness in the working-age population worldwide. With such a significant health impact, new drugs are required to halt the blinding threat posed by this visual disorder. The cause of diabetic retinopathy is multifactorial, and an optimal therapeutic would halt inflammation, cease photoreceptor cell dysfunction, and ablate vascular impairment. XMD8-92 is a small molecule inhibitor that blocks inflammatory activity downstream of ERK5 (extracellular signal-related kinase 5) and BRD4 (bromodomain 4). ERK5 elicits inflammation, is increased in Type II diabetics, and plays a pathologic role in diabetic nephropathy, while BRD4 induces retinal inflammation and plays a role in retinal degeneration. Further, we provide evidence that suggests both pERK5 and BRD4 expression are increased in the retinas of our STZ (streptozotocin)-induced diabetic mice. Taken together, we hypothesized that XMD8-92 would be a good therapeutic candidate for diabetic retinopathy, and tested XMD8-92 in a murine model of diabetic retinopathy. In the current study, we developed an in vivo treatment regimen by administering one 100 μL subcutaneous injection of saline containing 20 μM of XMD8-92 weekly, to STZ-induced diabetic mice. XMD8-92 treatments significantly decreased diabetes-mediated retinal inflammation, VEGF production, and oxidative stress. Further, XMD8-92 halted the degradation of ZO-1 (zonula occludens-1), which is a tight junction protein associated with vascular permeability in the retina. Finally, XMD8-92 treatment ablated diabetes-mediated vascular leakage and capillary degeneration, which are the clinical hallmarks of non-proliferative diabetic retinopathy. Taken together, this study provides strong evidence that XMD8-92 could be a potentially novel therapeutic for diabetic retinopathy.

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PLATELET FIBRONECTIN LEVELS AS A MARKER FOR THE PROGRESSION OF DIABETIC RETINOPATHY

10.1055/s-0038-1643097 ◽

1987 ◽

Author(s):

P Custodi ◽

G P Montecchio ◽

C Bendotti ◽

G Vandelli ◽

M T Tenconi ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Type I Diabetes ◽

Microvascular Complications ◽

Microvascular Complication ◽

Type I ◽

Extreme Groups ◽

Subendothelial Matrix ◽

The Difference ◽

Data Group

Aim of the study was to correlate fibronectin (Fn) and von Villebrand factor (vWf) levels measured in plasma and in platelets with the progression of diabetic retinopathy. Patients were classified in five groups reflecting the progression of this microvascular complication, on the basis of fluorangiographic findings (0 = no microangiopathy; 1= simple microangiopathy; 2= oedematous retinopathy; 3= ischaemic retinopathy; 4= ischaemic proliferative retinopathy). 43 patients were studied, 22 suffering from type I diabetes and 21 from type II diabetes, according to the classification of National Diabetes Data Group. Fn and vWf were measured in plasma and in platelet samples using an original double-sandwich microELISA method and expressed as micrograms/ml or as micrograms/10* platelets. Platelets were counted and solubilized with 0.5% Triton × 100. Bleeding time and platelet adhesion to glass beads were also evaluated on every patient. Intraplatelet Fn levels were reduced in retinopathies and correlate with the severity of the microvascular alteration, being the difference significant between the two extreme groups (p<0.05). vWf intraplatelet levels were also significantly lower in patients with severe microvascular complications (p<0.05). No significant differences were detected for plasma Fn and vWf levels in the 5 groups. Intraplatelet Fn and vWf levels may therefore be considered as markers of the severity of diabetic retinopathy. The leakage of Fn and vWf from activated platelet and the incorporation of these glycoproteins in the subendothelial matrix may be responsible for the worsening of this microvascular complication.

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