Inhibition of IL-6 trans-signaling prevents oxidative stress and lipid peroxidation in early diabetic retinopathy.

Abstract

Purpose : Diabetic retinopathy (DR) is a microvascular complication that is the leading cause of visual disability and blindness in diabetic patients. Hyperglycemia leads to oxidative stress, lipid peroxidation, and advanced glycation end (AGE) products. Our in-vitro studies have recently shown that IL-6 trans-signaling plays a significant role in oxidative stress and vascular inflammation. The purpose of this study was to determine if the inhibition of IL-6 trans-signaling using sgp130-Fc could prevent oxidative stress in diabetic mice.

Methods : Diabetes was induced in C57BL/6J mice using multiple Streptozotocin (STZ) injections. IL-6 levels and myeloperoxidase (MPO) activity were measured in the serum using ELISA assays. Total antioxidant capacity and reactive oxygen species (ROS) levels were quantified in the retinal sections using immunohistochemistry. AGE levels and protein carbonyl content were quantified in the vitreous fluid of diabetic mice.

Results : Upregulation of the inflammatory cytokine, IL-6, and MPO activity in diabetic mice was significantly attenuated with sgp130Fc treatment. Elevated ROS generation was observed in the diabetic mice retinas, which was prevented in the mice treated with sgp130Fc. An increase in ROS causes overproduction of malondialdehyde (MDA), which is one of the final products of lipid peroxidation in the cells. MDA levels were upregulated in plasma and retinas of diabetic mice and this increase was mitigated in the sgp130Fc treated mice. We also observed increased levels of AGEs and carbonyl content (a direct measure of oxidative stress) in the vitreous fluid of diabetic mice, which could be significantly attenuated using sgp130Fc treatment. Total antioxidant capacity in the plasma was observed to be significantly lower in diabetic mice than the control animals. Diabetic mice treated with sgp130Fc showed an increase in antioxidant levels, demonstrating the ability of sgp130Fc to mediate oxidative balance.

Conclusions : We found decreased antioxidant capacity, increased oxidative stress, increased protein oxidation and lipid peroxidation in diabetic mice, which could be prevented by the selective inhibition of IL6 trans-signaling using sgp130Fc-, fusion protein.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.