Aldose reductase: a novel therapeutic target for inflammatory pathologies

Abstract

Aldose reductase (AR), that catalyzes the rate limiting step of the polyol pathway of glucose metabolism, besides reducing glucose to sorbitol, reduces a number of lipid peroxidation - derived aldehydes and their glutathione conjugates. Recent studies suggest that apart from its involvement in diabetic complications, AR's catalytic activity plays a key role in a number of inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer. Furthermore, AR is overexpressed in human cancers such as liver, colon, breast, cervical and ovarian. Since AR inhibitors have already undergone up to phase-iii clinical trials for diabetic complications, they could be safe anti-inflammatory drugs. Therefore the future use of AR inhibitors in down-regulating major inflammatory pathologies such as cancer and cardiovascular diseases could relieve some of the major health concerns of worldwide.

Figure-1

Polyol pathway of glucose metabolism. In polyol pathway aldose reductase (AR) catalyzes the reduction of glucose to sorbitol. Sorbitol is converted to fructose by sorbitol dehydrogenase. Both the steps require NADPH and NAD+ as co-factors.

Figure-2

Role of aldose reductase in mediation of inflammatory signals. Cytokines, growth factors (GF), and lipopolysaccharide (LPS) cause oxidative stress via generation of ROS which forms toxic lipid aldehydes such as HNE by lipid peroxidation. HNE being highly electrophilic conjugates with cellular glutathione (GSH) spontaneously or catalyzed by GST to form GS-HNE. The reduced products of GS-aldehydes, GS-DHN, transduce inflammatory signaling via cascade of protein kinases leading to activation of NF-κB. Activation of NF-κB transcribes genes responsible for various inflammatory pathologies.