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Protection of Human Lens Epithelial Cells from Oxidative Stress Damage and Cell Apoptosis by KGF-2 through the
Shuyu Liu1, Zi Jin2, Ruyue Xia1
1Department of Ophthalmology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Abstract:
Oxidative stress exerts a significant influence on the pathogenesis of various cataracts by inducing degradation and aggregation of lens proteins and apoptosis of lens epithelial cells. Keratinocyte growth factor-2 (KGF-2) exerts a favorable cytoprotective effect against oxidative stress in vivo and in vitro. In this work, we investigated the molecular mechanisms of KGF-2 against hydrogen peroxide- (H2O2-) induced oxidative stress and apoptosis in human lens epithelial cells (HLECs) and rat lenses. KGF-2 pretreatment could reduce H2O2-induced cytotoxicity as well as reactive oxygen species (ROS) accumulation. KGF-2 also increases B-cell lymphoma-2 (Bcl-2), quinine oxidoreductase-1 (NQO-1), superoxide dismutase (SOD2), and catalase (CAT) levels while decreasing the expression level of Bcl2-associated X (Bax) and cleaved caspase-3 in H2O2-stimulated HLECs. LY294002, the phosphatidylinositol-3-kinase (PI3K)/Akt inhibitor, abolished KGF-2's effect to some extent, demonstrating that KGF-2 protected HLECs via the PI3K/Akt pathway. On the other hand, KGF-2 activated the Nrf2/HO-1 pathway by regulating the PI3K/Akt pathway. Silencing nuclear factor erythroid 2-related factor 2 (Nrf2) by targeted-siRNA and inhibiting heme oxygenase-1 (HO-1) through zinc protoporphyrin IX (ZnPP) significantly decreased cytoprotection of KGF-2. Furthermore, as revealed by lens organ culture assays, KGF-2 treatment decreased H2O2-induced lens opacity in a concentration-dependent manner. As demonstrated by these data, KGF-2 resisted H2O2-mediated apoptosis and oxidative stress in HLECs through Nrf2/HO-1 and PI3K/Akt pathways, suggesting a potential protective effect against the formation of cataracts.
Insights
Keratinocyte growth factor-2 (KGF-2) protects human lens epithelial cells from oxidative stress and apoptosis by activating the PI3K/Akt and Nrf2/HO-1 pathways. This suggests KGF-2 may prevent cataract formation.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Oxidative stress is a key factor in cataract development, leading to lens protein damage and cell death.
- Keratinocyte growth factor-2 (KGF-2) shows protective effects against oxidative stress in various cell types.
- Understanding KGF-2's protective mechanisms in lens cells is crucial for developing cataract therapies.
Purpose of the Study:
- To investigate the molecular mechanisms by which KGF-2 protects human lens epithelial cells (HLECs) against hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis.
- To explore the roles of the PI3K/Akt and Nrf2/HO-1 pathways in KGF-2-mediated cytoprotection.
- To evaluate the therapeutic potential of KGF-2 in preventing H2O2-induced lens opacity.
Main Methods:
- HLECs and rat lenses were pretreated with KGF-2 and exposed to H2O2.
- Cell viability, reactive oxygen species (ROS) levels, and apoptosis markers (Bcl-2, Bax, cleaved caspase-3) were assessed.
- The involvement of PI3K/Akt and Nrf2/HO-1 pathways was investigated using inhibitors (LY294002, ZnPP) and gene silencing (Nrf2-siRNA).
- Lens organ culture assays were performed to measure lens opacity.
Main Results:
- KGF-2 pretreatment significantly reduced H2O2-induced cytotoxicity, ROS accumulation, and apoptosis in HLECs.
- KGF-2 upregulated protective proteins (Bcl-2, NQO-1, SOD2, CAT) and downregulated pro-apoptotic proteins (Bax, cleaved caspase-3).
- KGF-2's protective effects were partially mediated by the PI3K/Akt pathway and further involved the Nrf2/HO-1 pathway.
- KGF-2 treatment decreased H2O2-induced lens opacity in a concentration-dependent manner.
Conclusions:
- KGF-2 effectively protects HLECs against H2O2-induced oxidative stress and apoptosis.
- The protective mechanisms involve the activation of both the PI3K/Akt and Nrf2/HO-1 signaling pathways.
- KGF-2 demonstrates potential as a therapeutic agent for preventing or treating cataracts.
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