Diabetic Retinopathy and Fisetin Study

Among the complications of diabetes, diabetic retinopathy (DR) is the most serious. As a vascular complication, this complication has a complex mechanism and is often caused by multiple factors. Relevant references suggest that the retina of diabetic patients responds rapidly to hyperglycemia, leading to an imbalance between pro- and antiangiogenic processes. Hyperglycemia can trigger a range of deficiencies in biological functions, including not only damage to retinal capillaries, but also abnormal vasoconstriction. The mechanisms involved may be related to increased secretion of angiogenic factors.

Angiogenic factors have been shown to play a regulatory role in the pathogenesis of retinal neovascularization (NV), including vascular endothelial growth factor (VEGF), the most important one. However, overexpression of VEGF results can lead to excessive formation of new blood vessels, which in turn results in vessel leakage. It is reported that the migration, proliferation, and tubular formation of human retinal endothelial cells (HRECs) are caused by VEGF through autocrine secretion during the disease process. In addition, VEGF can also regulate angiogenesis in other cells, mainly through paracrine secretion. It is evident that VEGF is a potential therapeutic target for angiogenesis during DR. Therefore, anti-VEGF drugs are considered as an ideal medication for the treatment of DR.

Fisetin is a flavonoid polyphenol molecule that is widely found in various fruits and vegetables such as strawberries, apples, onions, and cucumbers, with the highest content in strawberries. Several pharmacological benefits of fisetin have been reported, including anti-inflammatory, anti-apoptotic, antioxidant, antitumor, and anti-angiogenic effects.

Several studies have collectively concluded that fisetin decreases the progression of cancers via suppressing signaling pathways, such as NF-κB and PAK4. Besides, fisetin may exert its function by regulating cytokine production and inhibiting NF-κB activation in the retina. It also inhibits angiogenesis by inhibiting the VEGF/VEGFR signaling pathway and can be used as a candidate drug for inhibiting angiogenesis in retinoblastoma. This study by Meihua Lai et al aimed to investigate the role of fisetin in DR and potential mechanism.

Study Design

This study was designed to investigate the regulatory role of fisetin in regulating DR and explore the involved mechanism. First, 30 mM glucose was used to establish DR cell model in vitro. Cell counting kit 8 (CCK8) assay was utilized to study the effects of fisetin on cell viability through treating human retinal microvascular endothelial cells (HRMECs) with 25, 50, and 100 μM fisetin. Transwell and wound healing assays were used to detect the function of fisetin on the migration and angiogenesis on HG-induced HRMECs. Finally, OE-VEGF was used as a mimic of VEGF, and western blotting (WB) was used to verify the targeting genes of fisetin.

Key Findings

• Fisetin Inhibits HG-Induced Cell Viability in HRMECs: Fisetin decreases cell viability in a dose-dependent manner.
• Fisetin Inhibits HG-Induced Cell Migration in HRMECs: Fisetin could suppress cell migration, invasion, and progression in a dose-dependent manner.
• Fisetin Inhibits HG-Induced Angiogenesis in HRMECs: Relative to the HG group, fisetin at 25 μM, 50 μM, and 100 μM showed a dose-dependent effect on HG-induced angiogenesis.
• Fisetin Inhibits VEGF Expression in HRMECs: It was suggested that fisetin could inactivate VEGF expression in cells in a dose-dependent manner.
• Fisetin Attenuates HG-Induced Migration and Angiogenesis by Inhibiting VEGF in HRMECs: Fisetin inactivates the progression of migration and angiogenesis in a dose-dependent manner.

In this study, the viability of HRMECs was induced by HG. It has been reported that HG can induce a significant increase in the viability of retinal endothelial cells. However, this increase in cell viability can cause a range of functional impairments that further aggravate and exacerbate visual impairment. Cell migration is an important part of the formation of multicellular tissues and also plays an important role in wound healing. In our experiments, no significant increase in cell migration was found in the NC group, while HG induced an increase in the migration of HRMECs. Furthermore, fisetin inhibits the migratory ability of HG induced HRMECs in a dose-dependent manner. In conclusion, the present study found that fisetin prevents angiogenesis in DN by downregulating VEGF.

Source: Meihua Lai, Caifeng Lan, Junmu Zhong; Hindawi Journal of Ophthalmology Volume 2023

https://doi.org/10.1155/2023/7951928