转甲状腺素蛋白调控的糖尿病性视网膜病变通过 VEGFA/PI3K/AKT 通路。

Transthyretin-Regulated Diabetic Retinopathy Through the VEGFA/PI3K/AKT Pathway.

机构信息

Tianjin Eye Hospital, Tianjin, P. R. China.

Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin, P. R. China.

出版信息

Invest Ophthalmol Vis Sci. 2024 Jan 2;65(1):45. doi: 10.1167/iovs.65.1.45.

DOI:10.1167/iovs.65.1.45

PMID:38289614

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10833055/

Abstract

PURPOSE

Transthyretin (TTR) plays a regulatory role in a variety of diabetes-related diseases. The objective of this work was to probe whether TTR affects diabetic retinopathy (DR) through the VEGFA/PI3K/AKT pathway.

METHODS

High glucose (HG, 25 mM) was used to treat human retinal microvascular endothelial cells (hRMECs) and C57BL/6J mice were intraperitoneally injected with STZ (50 mg/kg) to construct a DR model. In vitro, the effect of TTR on DR was evaluated by measuring hRMEC proliferation, migration, and angiogenesis. The changes in retinal tissue were observed by hematoxylin and eosin staining in vivo. ELISA, immunohistochemistry, and immunofluorescence staining were used to measure VEGFA or CD31 levels. The levels of all proteins were evaluated through Western blot.

RESULTS

The increase of proliferation, migration, and angiogenesis and decrease of apoptosis in hRMECs caused by HG were notably reversed by TTR. TTR greatly impeded HG-raised VEGFA, PI3K p-p85, and p-AKT in hRMECs. Inhibition of TTR further exacerbated the effect of HG-induced hRMECs. Inhibition of VEGFA reversed the effect of HG-induced hRMECs. VEGFA neutralized the function of TTR on cell proliferation, apoptosis, migration, and angiogenesis in HG-triggered hRMECs. It was further confirmed in vivo that TTR can alleviate the occurrence of DR in diabetic mice models.

CONCLUSIONS

TTR significantly restrained the progression of DR via molecular modulation of the VEGFA/PI3K/AKT axis.

摘要

目的

转甲状腺素蛋白（TTR）在多种与糖尿病相关的疾病中发挥调节作用。本研究旨在探讨 TTR 是否通过 VEGFA/PI3K/AKT 通路影响糖尿病视网膜病变（DR）。

方法

用高糖（25 mM）处理人视网膜微血管内皮细胞（hRMECs），并用链脲佐菌素（STZ，50 mg/kg）腹腔注射构建 DR 模型。在体外，通过测量 hRMEC 增殖、迁移和血管生成来评估 TTR 对 DR 的影响。体内通过苏木精和伊红染色观察视网膜组织的变化。ELISA、免疫组化和免疫荧光染色用于测量 VEGFA 或 CD31 水平。通过 Western blot 评估所有蛋白质的水平。

结果

HG 引起的 hRMEC 增殖、迁移和血管生成增加以及细胞凋亡减少明显被 TTR 逆转。TTR 显著抑制了 HG 升高的 hRMECs 中的 VEGFA、PI3K p-p85 和 p-AKT。TTR 抑制进一步加剧了 HG 诱导的 hRMECs 的作用。VEGFA 抑制逆转了 HG 诱导的 hRMECs 的作用。VEGFA 中和了 TTR 在 HG 触发的 hRMECs 中对细胞增殖、凋亡、迁移和血管生成的作用。在体内进一步证实，TTR 可以减轻糖尿病小鼠模型中 DR 的发生。