Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy

Jiayuan Li; Kuangqi Chen; Xiang Li; Xuhong Zhang; Liyue Zhang; Qianjie Yang; Yutong Xia; Chen Xie; Xiawei Wang; Jianping Tong; Ye Shen

doi:10.1038/s41420-023-01717-2

Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy

Cell Death Discov. 2023 Nov 17;9(1):418. doi: 10.1038/s41420-023-01717-2.

Authors

Jiayuan Li^#^{1

2}, Kuangqi Chen^#¹, Xiang Li¹, Xuhong Zhang¹, Liyue Zhang¹, Qianjie Yang¹, Yutong Xia¹, Chen Xie¹, Xiawei Wang¹, Jianping Tong³, Ye Shen⁴

Affiliations

¹ Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
² Department of Cardiology, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
³ Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China. idrtong@zju.edu.cn.
⁴ Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China. idrshen@zju.edu.cn.

^# Contributed equally.

Abstract

In the early stages of diabetic retinopathy (DR), diabetes-related hyperglycemia directly inhibits the AKT signaling pathway by increasing oxidative stress or inhibiting growth factor expression, which leads to retinal cell apoptosis, nerve proliferation and fundus microvascular disease. However, due to compensatory vascular hyperplasia in the late stage of DR, the vascular endothelial growth factor (VEGF)/phosphatidylinositol 3 kinase (PI3K)/AKT cascade is activated, resulting in opposite levels of AKT regulation compared with the early stage. Studies have shown that many factors, including insulin, insulin-like growth factor-1 (IGF-1), VEGF and others, can regulate the AKT pathway. Disruption of the insulin pathway decreases AKT activation. IGF-1 downregulation decreases the activation of AKT in DR, which abrogates the neuroprotective effect, upregulates VEGF expression and thus induces neovascularization. Although inhibiting VEGF is the main treatment for neovascularization in DR, excessive inhibition may lead to apoptosis in inner retinal neurons. AKT pathway substrates, including mammalian target of rapamycin (mTOR), forkhead box O (FOXO), glycogen synthase kinase-3 (GSK-3)/nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa-B (NF-κB), are a research focus. mTOR inhibitors can delay or prevent retinal microangiopathy, whereas low mTOR activity can decrease retinal protein synthesis. Inactivated AKT fails to inhibit FOXO and thus causes apoptosis. The GSK-3/Nrf2 cascade regulates oxidation and inflammation in DR. NF-κB is activated in diabetic retinas and is involved in inflammation and apoptosis. Many pathways or vital activities, such as the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) signaling pathways, interact with the AKT pathway to influence DR development. Numerous regulatory methods can simultaneously impact the AKT pathway and other pathways, and it is essential to consider both the connections and interactions between these pathways. In this review, we summarize changes in the AKT signaling pathway in DR and targeted drugs based on these potential sites.

Publication types

Review