The P2X7 Receptor: A Promising Pharmacological Target in Diabetic Retinopathy

Abstract

Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting.

Keywords: P2X7; angiogenesis; diabetic retinopathy; inflammation; neural damage.

Figure 1

Schematic rendition of the main causative events in the pathogenesis of diabetic retinopathy.

Figure 2

A dysregulation of the ATP-P2X7R axis is a main factor in the pathogenesis of diabetic retinopathy. Hyperglycemia is a cause of chronic inflammation, tissue damage, and cytokine (e.g., IL-1β or TNF-α) release. These events promote ATP release. For example, ATP release can be promoted by ligation of CD40 by CD40L on the plasma membrane of Müller cells or by the activation of the P2X7R itself. The increase in the extracellular ATP (eATP) concentration amplifies inflammation by activating the P2X7R expressed in the retina by several cell types (e.g., Müller cells, astrocytes, microglia, and pericytes), thus causing further release of cytokines and vascular endothelial growth factor (VEGF). VEGF in turn causes a breakdown of the blood–retinal barrier (BRB) promoting the formation of inflammatory exudate and inflammatory cell migration form circulation.