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IGF-1 Signaling via the PI3K/Akt Pathway Confers Neuroprotection in Human Retinal Pigment Epithelial Cells Exposed to Sodium Nitroprusside Insult

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Abstract

The pathological increase in the levels of the second messenger nitric oxide (NO) in the vitreous cavity and retina leads to injury and cell death of the retinal pigment epithelium (RPE) cells and eventually may contribute to the occurrence and development of diabetic retinopathy. In this study, we developed a cellular model of retinopathy using D407 cells (a human RPE cell line) exposed to sodium nitroprusside (SNP) and investigated the protective effect of the insulin-like growth factor-1 (IGF-1) towards this insult. Cell death and apoptosis were examined by the methyl thiazolyl tetrazolium assay and Hoechst staining, respectively. Specific inhibitors were used and phosphorylation of relevant signaling proteins was determined by Western blotting. SNP, in a concentration-dependent fashion, increased the production of reactive oxygen species (ROS) and lipid peroxidation process causing cell death by apoptosis of D407 cells. IGF-1, in a time- and dose-dependent manner, conferred protection towards SNP-mediated insult. Both phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) were activated by IGF-1 in relation to the protective effect. Blockade of the PI3K/Akt pathway abolished the protective effect of IGF-1 whereas inhibition of the MAPK pathway was ineffective. SNP decreased the phosphorylation of Akt in the cells while IGF-1 reversed this inhibitory effect. These results indicate that the protective effect of IGF-1 on D407 exposed to SNP insult is mediated by the PI3K/Akt pathway. This proposal may be exploited in the clinic to improve the viability of insulted retinal cells for maintaining physiological vision.

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Abbreviations

Akt:

Protein kinase B

BRB:

Blood retinal barrier

DCFH-DA:

2′,7′-dichlorofluoresceindiacetate

ERK1/2:

Extracellular regulated protein kinases 1/2

IGF-1:

Insulin-like growth factor-1

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

NO:

Nitric oxide

NOS:

Nitric oxide synthases

PI3K:

Phosphatidylinositol 3-kinase

ROS:

Reactive oxygen species

RPE:

Retinal pigmented epithelium

SNP:

Sodium nitroprusside

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Disclosure Statement, Funding, and Role of Funding Source

This work was supported by Funding from Guangdong Science and Technology Department (No. 2011B050200005), National Natural Science Fund of China (No 31371088); Funding of State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Funding from Chinese State Administration of Foreign Experts Affairs for high end expert (PJL).

The sources of funding had no role in the design and conduct of this project or in the preparation of the manuscript.

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Authors and Affiliations

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China

    Haitao Wang, Sufen Liao, Ruojun Geng, Yongxin Zheng, Rifang Liao, Fengxia Yan & Wenhua Zheng

  2. Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, Melbourne, VIC, 3083, Australia

    Thilini Thrimawithana & Peter J. Little

  3. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    Zhong-Ping Feng

  4. School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Philip Lazarovici

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  1. Haitao Wang
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  2. Sufen Liao
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  11. Wenhua Zheng
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Correspondence to Wenhua Zheng.

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Haitao Wang and Sufen Liao Authors contributed equally to this work.

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Wang, H., Liao, S., Geng, R. et al. IGF-1 Signaling via the PI3K/Akt Pathway Confers Neuroprotection in Human Retinal Pigment Epithelial Cells Exposed to Sodium Nitroprusside Insult. J Mol Neurosci 55, 931–940 (2015). https://doi.org/10.1007/s12031-014-0448-7

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