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.
Highlights
Cataract, primarily age-related, is the main reason for visual impairment and blindness across the world [1]
We adopted H2O2-mediated human lens epithelial cells (HLECs) and rat lenses as study models and for the first time demonstrated that Keratinocyte growth factor−2 (KGF-2) may protect HLECs against oxidative stress-mediated apoptosis via the Akt/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and may prove beneficial for treating cataracts associated with oxidative stress
HLECs pretreated by KGF-2 exhibited a concentration-dependent protective effect against H2O2 damage (Figure 1(c))
Summary
Primarily age-related, is the main reason for visual impairment and blindness across the world [1]. Oxidative stress triggers apoptosis for human lens epithelial cells (HLECs) by altering the internal environment. It is considered the common molecular basis for cataract initiation as well as progression [5]. Protecting HLECs against H2O2-induced oxidative stress and apoptosis is a potential solution to postpone cataract development. Recent studies demonstrate that growth factors possibly reduce oxidant-induced lung damage by suppressing apoptosis [15]. We adopted H2O2-mediated HLECs and rat lenses as study models and for the first time demonstrated that KGF-2 may protect HLECs against oxidative stress-mediated apoptosis via the Akt/Nrf2/HO-1 pathway and may prove beneficial for treating cataracts associated with oxidative stress
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