Potential of Carbonic Anhydrase Inhibitors in the Treatment of Oxidative Stress and Diabetes

Abstract

Increased oxidative stress has been recognized as a major contributing factor to various pathological conditions including diabetes and its complications. Although, several mechanisms contribute to increased oxidative stress (OxS) in diabetes, increased levels of glucose and altered metabolic activities are major contributors to production of reactive oxygen species (ROS) and OxS. The identity of the target cells and metabolic pathways involved in ROS production provide a venue for treatment of the underlying causes and mitigation of diabetes complications including diabetic retinopathy. Diabetic retinopathy affects retinal neurovasculature, and loss of retinal vascular pericytes (PC) has been recognized as one of the early targets. We have shown that retinal PC are most sensitive to high glucose conditions in culture compared with retinal vascular endothelial cells (EC) and astrocytes (AC). We have proposed that retinal PC may differ in their metabolism of glucose compared with EC. Pericytes likely prefer oxidative metabolism for energy production, especially under high glucose conditions, generating excess ROS that drives their demise. This is mediated, in part, through activation of hexose biosynthetic pathway, enhanced O-GlcNAc modification and stabilization of P53, and attenuation of the Warburg effect. In support of this hypothesis, we recently showed retinal PC, but not EC, generate more superoxide under high glucose conditions. We also showed inhibition of carbonic anhydrases (CA) protects PC from adverse effects of high glucose. The inhibition of CA, especially those in the mitochondria (mCA), limits the production of bicarbonate that is essential for the first step of oxidative metabolism in the mitochondria. Thus, targeting of the mCA may provide a unique opportunity for modulation of PC metabolism mitigating the development and progression of diabetic retinopathy and likely other complications of diabetes.