Role and Regulation of Nox4 in the retina during diabetes

• Applicant: Dr. Anne Rübsam
• Subject Area: Ophthalmology ; Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407606212

The prevalence of type 2 diabetes is increasing at an alarming rate with approximately 93 million people affected worldwide and 28 million of them having vision-threatening diabetic retinopathy (DR), the major ocular complication of diabetes. Therapies utilizing antibodies against the growth factor Vascular endothelial growth factor (VEGF) have tremendously improved the treatment of proliferative diabetic retinopathy and macular edema, the two late stages of DR, but there are still no therapies targeting early stages of the disease to prevent alterations of the neural retina and thereby preserve visual function. Several reviews have summarized that retinal dysfunction associated with diabetes may be viewed as a change in the retinal neurovascular unit. The neurovascular unit refers to the physiological and biochemical relationship among blood-vessel endothelial cells and pericytes, astrocytes, Müller glial cells, and neurons which are intimately associated to influence the blood– retina barrier. Therefore, new therapeutic approaches that address vascular dysfunction and neural degeneration are required. Hyperglycemia-dependent generation of reactive metabolites are known to cause excessive reactive oxygen species (ROS) production, which are likely to be a key contributor to the development of DR. NADPH (nicotinamide adenine dinucleotide phosphate) enzymes generate ROS and they are known to be widely distributed throughout the retina. Nox 4, one of the 7 isoforms of the Nox family, has been implicated in numerous pathways such as signal transduction, cell differentiation and death. Evidence that Nox4 is an important source of ROS in the retina during DR was provided by a study demonstrating that depletion of Nox4 significantly decreased ROS production, VEGF expression and reduced vascular permeability in diabetic rodents. To date most studies on the role of Nox4 in the retina utilized retinal or other organ derived endothelial cells, which contribute to the vascular changes associated with DR. Still today, there is a gap of knowledge regarding the role and regulation of Nox4 in the retina outside of the vasculature, celltypes which are particularly susceptible to metabolic changes and contribute to the early pathophysiological changes in DR. Thus, I aim to develop a complete picture of Nox4 activity in the retina during diabetes by evaluating the role and regulation of Nox4 as major source of ROS in the retinal neurons, Müller cells and pericytes under diabetic conditions in culture and in two rodent models of diabetes (type 1 & 2). I further want to evaluate the rationale of Nox4 inhibition in preventing oxidative stress induced early neurodegenerative changes in DR. If such a treatment could be realized, it may be possible to promote retinal cell survival in DR at the earliest stages of its development.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Dr. Patrice Fort