Protection of Human Lens Epithelial Cells from Oxidative Stress Damage and Cell Apoptosis by KGF‐2 through the Akt/Nrf2/HO‐1 Pathway
Shuyu Liu, Zi Jin, Ruyue Xia, Zhuoni Zheng, Yi Zha, Qiang Wang, Xinbei Wan, Hui Yang, Jianqiu Cai
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‐ (H 2 O 2 ‐) induced oxidative stress and apoptosis in human lens epithelial cells (HLECs) and rat lenses. KGF‐2 pretreatment could reduce H 2 O 2 ‐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 H 2 O 2 ‐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 H 2 O 2 ‐induced lens opacity in a concentration‐dependent manner. As demonstrated by these data, KGF‐2 resisted H 2 O 2 ‐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.