Prolonged Exposure to High Glucose Induces Premature Senescence Through Oxidative Stress and Autophagy in Retinal Pigment Epithelial Cells

IF 2.9 4区 医学 Q3 IMMUNOLOGY Archivum Immunologiae et Therapiae Experimentalis Pub Date : 2023-08-28 DOI:10.1007/s00005-023-00686-9
Chien-Chih Chiu, Kai-Chun Cheng, Yi-Hsiung Lin, Chen-Xi He, Yung-Ding Bow, Chia-Yang Li, Chang-Yi Wu, Hui-Min David Wang, Shwu-Jiuan Sheu
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Abstract

Chronic hyperglycemia involves persistent high-glucose exposure and correlates with retinal degeneration. It causes various diseases, including diabetic retinopathy (DR), a major cause of adult vision loss. Most in vitro studies have investigated the damaging short-term effects of high glucose exposure on retinal pigment epithelial (RPE) cells. DR is also a severe complication of diabetes. In this study, we established a model with prolonged high-glucose exposure (15 and 75 mM exogenous glucose for two months) to mimic RPE tissue pathophysiology in patients with hyperglycemia. Prolonged high-glucose exposure attenuated glucose uptake and clonogenicity in ARPE-19 cells. It also significantly increased reactive oxygen species levels and decreased antioxidant protein (superoxide dismutase 2) levels in RPE cells, possibly causing oxidative stress and DNA damage and impairing proliferation. Western blotting showed that autophagic stress, endoplasmic reticulum stress, and genotoxic stress were induced by prolonged high-glucose exposure in RPE cells. Despite a moderate apoptotic cell population detected using the Annexin V-staining assay, the increases in the senescence-associated proteins p53 and p21 and SA-β-gal-positive cells suggest that prolonged high-glucose exposure dominantly sensitized RPE cells to premature senescence. Comprehensive next-generation sequencing suggested that upregulation of oxidative stress and DNA damage-associated pathways contributed to stress-induced premature senescence of ARPE-19 cells. Our findings elucidate the pathophysiology of hyperglycemia-associated retinal diseases and should benefit the future development of preventive drugs.

Graphical Abstract

Prolonged high-glucose exposure downregulates glucose uptake and oxidative stress by increasing reactive oxygen species (ROS) production through regulation of superoxide dismutase 2 (SOD2) expression. Autophagic stress, ER stress, and DNA damage stress (genotoxic stress) are also induced by prolonged high-glucose exposure in RPE cells. Consequently, multiple stresses induce the upregulation of the senescence-associated proteins p53 and p21. Although both apoptosis and premature senescence contribute to high glucose exposure-induced anti-proliferation of RPE cells, the present work shows that premature senescence rather than apoptosis is the dominant cause of RPE degeneration, eventually leading to the pathogenesis of DR.

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通过氧化应激和视网膜色素上皮细胞的自噬,长期暴露于高糖环境中诱导过早衰老
慢性高血糖包括持续的高糖暴露,并与视网膜变性相关。它会导致各种疾病,包括糖尿病视网膜病变(DR),这是导致成人视力丧失的主要原因。大多数体外研究都研究了高葡萄糖暴露对视网膜色素上皮细胞(RPE)的短期破坏性影响。DR也是糖尿病的一种严重并发症。在这项研究中,我们建立了一个长时间高糖暴露(15和75 mM外源性葡萄糖两个月)的模型来模拟高血糖患者的RPE组织病理生理。长时间的高糖暴露降低了ARPE-19细胞的葡萄糖摄取和克隆原性。它还显著增加RPE细胞中的活性氧水平,降低抗氧化蛋白(超氧化物歧化酶2)水平,可能引起氧化应激和DNA损伤,损害增殖。Western blot结果显示,长时间高糖暴露可诱导RPE细胞自噬应激、内质网应激和基因毒性应激。尽管使用膜联蛋白v染色法检测到适度的凋亡细胞群,但衰老相关蛋白p53和p21以及SA-β-gal阳性细胞的增加表明,长时间的高糖暴露主要使RPE细胞对过早衰老敏感。全面的下一代测序表明,氧化应激和DNA损伤相关途径的上调有助于应激诱导的ARPE-19细胞过早衰老。我们的研究结果阐明了高血糖相关视网膜疾病的病理生理学,并有助于未来预防药物的开发。长期高糖暴露通过调节超氧化物歧化酶2 (SOD2)的表达,增加活性氧(ROS)的产生,从而下调葡萄糖摄取和氧化应激。自噬应激、内质网应激和DNA损伤应激(基因毒性应激)也可由RPE细胞长期高糖暴露诱导。因此,多重应激诱导衰老相关蛋白p53和p21的上调。虽然细胞凋亡和过早衰老都有助于高糖暴露诱导的RPE细胞的抗增殖,但目前的研究表明,过早衰老而不是细胞凋亡是RPE变性的主要原因,最终导致DR的发病机制。
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来源期刊
CiteScore
5.90
自引率
0.00%
发文量
26
审稿时长
>12 weeks
期刊介绍: Archivum Immunologiae et Therapiae Experimentalis (AITE), founded in 1953 by Ludwik Hirszfeld, is a bimonthly, multidisciplinary journal. It publishes reviews and full original papers dealing with immunology, experimental therapy, immunogenetics, transplantation, microbiology, immunochemistry and ethics in science.
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