The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice

Choi, Jeong A; Younghae, Chung; Byun, Hyae-Ran; Park, Hwangseo; Koh, Jae‐Young; Yoon, Young Hee

doi:10.1016/j.taap.2016.12.004

Cited by 15 publications

(14 citation statements)

References 44 publications

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“…Increased fluorescein leakage was observed at a late phase in retinas of STZ diabetic mice, compared with controls, which was significantly attenuated upon UDCA treatment (Figures 1(a) and 1(b)). To evaluate the effect of UDCA on retinal microvasculature in diabetic mice, we measured the linear capillary density by counting the number of capillaries intersected by a 500 μ m line on fluorescein isothiocyanate (FITC) images at 8 weeks after STZ injection [36, 37]. Linear capillary density was decreased in nontreated diabetic mice, compared with controls, but not in UDCA-treated mice (Figures 2(a) and 2(b)).…”

Section: Resultsmentioning

confidence: 99%

“…We sacrificed mice 8 weeks after STZ injection, when we evaluated as the time-point of prominent vascular change, from our previous experiment [36]. Anesthesia was performed via intramuscular injection of 0.3 ml of Zoletil (diluted 1 : 5) and cardiac perfusion with 0.5 ml of 15 mg/ml fluorescein-dextran (2,000 kDa, #FD2000S, Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…mLDL prepared in PBS and incubated with CuCl 2 was used as a control. The doses of AGE or mLDL used were based on data from a previous study by our group [36], while 100 μ M UDCA was the lowest concentration effective in attenuating expression of UPR markers in cultured retinal pericytes.…”

Section: Methodsmentioning

confidence: 99%

“…Eyeballs were enucleated for evaluation of UPR markers at 4 weeks after STZ injection, while those for evaluation of inflammatory cytokines were harvested at 8 weeks [36]. Pericytes and whole eyeball tissues were lysed in radioimmunoprecipitation assay (RIPA) buffer (20 mM Tris-Cl pH 7.4, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 μ M Na 3 VO 4 , 1 μ g/ml leupeptin, and 1 mM phenylmethylsulfonyl fluoride).…”

Section: Methodsmentioning

confidence: 99%

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Ursodeoxycholic Acid Attenuates Endoplasmic Reticulum Stress-Related Retinal Pericyte Loss in Streptozotocin-Induced Diabetic Mice

Younghae

Choi

Koh

et al. 2017

Journal of Diabetes Research

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Loss of pericytes, an early hallmark of diabetic retinopathy (DR), results in breakdown of the blood-retinal barrier. Endoplasmic reticulum (ER) stress may be involved in this process. The purpose of this study was to examine the effects of ursodeoxycholic acid (UDCA), a known ameliorator of ER stress, on pericyte loss in DR of streptozotocin- (STZ-) induced diabetic mice. To assess the extent of DR, the integrity of retinal vessels and density of retinal capillaries in STZ-induced diabetic mice were evaluated. Additionally, induction of ER stress and the unfolded protein response (UPR) were assessed in diabetic mice and human retinal pericytes exposed to advanced glycation end products (AGE) or modified low-density lipoprotein (mLDL). Fluorescein dye leakage during angiography and retinal capillary density were improved in UDCA-treated diabetic mice, compared to the nontreated diabetic group. Among the UPR markers, those involved in the protein kinase-like ER kinase (PERK) pathway were increased, while UDCA attenuated UPR in STZ-induced diabetic mice as well as AGE- or mLDL-exposed retinal pericytes in culture. Consequently, vascular integrity was improved and pericyte loss reduced in the retina of STZ-induced diabetic mice. Our findings suggest that UDCA might be effective in protecting against DR.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ursodeoxycholic Acid Attenuates Endoplasmic Reticulum Stress-Related Retinal Pericyte Loss in Streptozotocin-Induced Diabetic Mice

Younghae

Choi

Koh

et al. 2017

Journal of Diabetes Research

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“…However, these therapies are often started in late stages of DR, and are designed to prevent further deterioration rather than restore impaired vision [70]. On the other hand, intensive treatment of diabetes may prevent onset and progression of DR as shown by the Diabetes Control and Complications Trial (DCCT) and UKPDS studies [71].…”

Section: Therapeutic Viewpointsmentioning

confidence: 99%

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

Chen

et al. 2018

Cell Physiol Biochem

153

106

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Diabetic retinopathy (DR) is a common and devastating microvascular complication of diabetes and a major cause of acquired blindness in young adults. Advanced glycation end products (AGEs) accumulated under hyperglycemic conditions are thought to play an important role in the pathogenesis of DR. AGEs can exert their deleterious effects by acting directly to induce aberrant crosslinking of extracellular matrix proteins, to increase vascular stiffness, altering vascular structure and function. Moreover, AGEs binding to the receptor for AGEs (RAGE) evokes intensive intracellular signaling cascades that leading to endothelial dysfunction, elaboration of key proinflammatory cytokines and proangiogenic factors, mediating pericyte apoptosis, vascular inflammation and angiogenesis, as well as breakdown of the inner blood-retinal barrier (BRB), the end result of all these events is damage to the neural and vascular components of the retina. Elucidation of AGE-induced mechanisms will help in the understanding of the complex cellular and molecular pathogenesis associated with DR. Novel anti-AGEs agents or AGE crosslink “breakers” are being investigated, it is hoped that in next few years, some of these promising therapies will be successfully applied in clinical context, aiming to reduce the major economical and medical burden caused by DR.

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Genome‐wide pathogenesis interpretation using a heat diffusion‐based systems genetics method and implications for gene function annotation

Yuan

Zhang

et al. 2020

Molec Gen & Gen Med

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Background: Genetics is best dedicated to interpreting pathogenesis and revealing gene functions. The past decade has witnessed unprecedented progress in genetics, particularly in genome-wide identification of disorder variants through Genome-Wide Association Studies (GWAS) and Phenome-Wide Association Studies (PheWAS). However, it is still a great challenge to use GWAS/PheWAS-derived data to elucidate pathogenesis. Methods: In this study, we used HotNet2, a heat diffusion-based systems genetics algorithm, to calculate the networks for disease genes obtained from GWAS and PheWAS, with an attempt to get deeper insights into disease pathogenesis at a molecular level. Results: Through HotNet2 calculation, significant networks for 202 (for GWAS) and 167 (for PheWAS) types of diseases were identified and evaluated, respectively. The GWAS-derived disease networks exhibit a stronger biomedical relevance than PheWAS counterparts. Therefore, the GWAS-derived networks were used for pathogenesis interpretation by integrating the accumulated biomedical information. As a result, the pathogenesis for 64 diseases was elucidated in terms of mutation-caused abnormal transcriptional regulation, and 47 diseases were preliminarily interpreted in terms of mutation-caused varied protein-protein interactions. In addition, 3,802 genes (including 46 function-unknown genes) were assigned with new functions by disease network information, some of which were validated through mice gene knockout experiments. Conclusions: Systems genetics algorithm HotNet2 can efficiently establish genotype-phenotype links at the level of biological networks. Compared with original GWAS/PheWAS results, HotNet2-calculated disease-gene associations have stronger biomedical significance, hence provide better interpretations for the pathogenesis of genome-wide variants, and offer new insights into gene functions as well. These results are also helpful in drug development. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice

Cited by 15 publications

References 44 publications

Ursodeoxycholic Acid Attenuates Endoplasmic Reticulum Stress-Related Retinal Pericyte Loss in Streptozotocin-Induced Diabetic Mice

Ursodeoxycholic Acid Attenuates Endoplasmic Reticulum Stress-Related Retinal Pericyte Loss in Streptozotocin-Induced Diabetic Mice

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

Genome‐wide pathogenesis interpretation using a heat diffusion‐based systems genetics method and implications for gene function annotation

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