Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

Abstract

Amiodarone is one of the most effective anti-arrhythmic drugs available, but its clinical applications are limited by toxic side effects including optic toxicity. The purpose of this study was to investigate the toxic effect of amiodarone on D407 cells (a human retinal pigmented epithelial (RPE) cell line) and the mechanisms of the protective effect of insulin-like growth factor-1 (IGF-1). EXPERIMENTAL APPROACHThe involvement of the kinases, Akt and ERK, was analysed by Western blot. Intracellular accumulation of ROS was measured using fluorophotometric quantification. A pharmacological approach with inhibitors was used to investigate the pathways involved in the protective action of IGF-1. KEY RESULTSAmiodarone concentration-dependently augmented the production of ROS, lipid peroxidation and apoptosis in D407 cells. IGF-1 time-and concentration-dependently reversed these effects of amiodarone and protected D407 cells from amiodarone-mediated toxicity. Amiodarone inhibited the pAkt but not pErk, and IGF-1 reversed this inhibitory effect of amiodarone. However, IGF-1 failed to suppress amiodarone-induced cytotoxicity in the presence of PI3K/Akt inhibitor LY294002 suggesting the direct involvement of the PI3K/Akt pathway. Furthermore, in vivo rat flash electroretinogram (FERG) recordings showed that IGF-1 reverses the amiodarone-induced decrease in a-and b-waves. The immunocytochemistry findings confirmed that vitreous IGF-1 injections promote the survival of RPE cells in rat retina treated with amiodarone. CONCLUSION AND IMPLICATIONSIGF-1 can protect RPE cells from amiodarone-mediated injury via the PI3K/Akt pathway in vivo and in vitro. IGF-1 has potential as a protective drug for the prevention and treatment of amiodarone-induced optic toxicity.Abbreviations FERG, flash electroretinogram; IGF-1, insulin-like growth factor-1; INL, inner nuclear layer; IPL, inner plexiform layer; RGCs, retinal ganglionic cells; RPE, retinal pigmented epithelium

Chrysin Ameliorates Malfunction of Retinoid Visual Cycle through Blocking Activation of AGE-RAGE-ER Stress in Glucose-Stimulated Retinal Pigment Epithelial Cells and Diabetic Eyes

“…Interestingly, this study showed that glucose temporally attenuated the induction of angiogenic IGF-1 of RPE cells, which was reversed by treating chrysin. A recent study shows that IGF-1 protects RPE cells from amiodarone-mediated injury via activation of PI3K/Akt signaling [ 40 ]. In this study, IGF-1 had potential as a protective agent for deterring the AGE-mediated toxicity of glucose.…”

Dietary methionine affects growth and the expression of key genes involved in hepatic lipogenesis and glucose metabolism in cobia (Rachycentron canadum)

“…Previous studies have suggested that Met significantly influences insulin‐like growth factor‐I (IGF‐I) gene expression (Wang et al, ). IGF‐I binds with its receptor in the cell membrane to activate the PI3K/Akt pathway (Liao et al, ), which plays a vital role in regulating glucose metabolism and maintaining glucose homeostasis (Bruce & Hanson, ; Hamann et al, ). The phosphorylation of Akt can induce the translocation of glucose from the cytoplasm to the plasma membrane through glucose transporter 4 (Patki et al, ).…”

Dihydromyricetin protects HUVECs of oxidative damage induced by sodium nitroprusside through activating PI3K/Akt/FoxO3a signalling pathway

“…In the presence of serum and growth factors, Akt was phosphorylated and in turn phosphorylates FoxO3a, then FoxO3a was transported from the nucleus to the cytoplasm, where FoxO3a down‐regulates the expression of pro‐apoptosis molecules, such as Bax and Bcl‐2 . On the contrary, oxidative stress can induce FoxO3a from the cytoplasm to the nucleus, activate the target genes of FoxO3a, such as the pro‐apoptotic gene Bim, and induce cell apoptosis . The role of FoxO3a in oxidative stress‐induced cardiotoxicity has received attention.…”

“…35,36 On the contrary, oxidative stress can induce FoxO3a from the cytoplasm to the nucleus, activate the target genes of FoxO3a, such as the pro-apoptotic gene Bim, and induce cell apoptosis. 37,38 The role of Figure 6). SNP induced FoxO3a translocation into the nucleus, increased the expression and activation of cleaved caspase-3, and inhibited the expression of Bcl-2, but had no effect on the expression of Bax (Figure 7).…”