Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders

Abstract

Oxidative stress-induced inflammation is a major contributor to several disease conditions including sepsis, carcinogenesis and metastasis, diabetic complications, allergic asthma, uveitis and after cataract surgery posterior capsular opacification. Since reactive oxygen species (ROS)-mediated activation of redox-sensitive transcription factors and subsequent expression of inflammatory cytokines, chemokines and growth factors are characteristics of inflammatory disorders, we envisioned that by blocking the molecular signals of ROS that activate redox-sensitive transcription factors, various inflammatory diseases could be ameliorated. We have indeed demonstrated that ROS-induced lipid peroxidation-derived lipid aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and their glutathione-conjugates (e.g. GS-HNE) are efficiently reduced by aldose reductase to corresponding alcohols which mediate the inflammatory signals. Our results showed that inhibition of aldose reductase (AKR1B1) significantly prevented the inflammatory signals induced by cytokines, growth factors, endotoxins, high glucose, allergens and auto-immune reactions in cellular as well as animal models. We have demonstrated that AKR1B1 inhibitor, fidarestat, significantly prevents tumor necrosis factor-alpha (TNF-α)-, growth factors-, lipopolysachharide (LPS)-, and environmental allergens-induced inflammatory signals that cause various inflammatory diseases. In animal models of inflammatory diseases such as diabetes, cardiovascular, uveitis, asthma, and cancer (colon, breast, prostate and lung) and metastasis, inhibition of AKR1B1 significantly ameliorated the disease. Our results from various cellular and animal models representing a number of inflammatory conditions suggest that ROS-induced inflammatory response could be reduced by inhibition of AKR1B1, thereby decreasing the progression of the disease and if the therapy is initiated early, the disease could be eliminated. Since fidarestat has already undergone phase III clinical trial for diabetic neuropathy and found to be safe, though clinically not very effective, our results indicate that it can be developed for the therapy of a number of inflammation-related diseases. Our results thus offer a novel therapeutic approach to treat a wide array of inflammatory diseases.

Figure 1

Schematic presentation of role of aldose reductase (AKR1B1) in the mediation of inflammatory pathologies (for details see the text). AKR1B1, aldose reductase; GF, growth factors; TNF-α, tumor necrosis factor-alpha; LPS, Lipopolysachharide; ROS, reactive oxygen species; LDA, lipid peroxidation- derived aldehydes; HNE, 4-hydroxy-trans-2-nonenal; GS-HNE, glutathione-4-hydroxy-trans-2-nonenal; GS-DHN, glutathionyl-1,4-dihydroxynonene; PI3K, phosphoinositide 3-kinases; PKC, protein kinase C; PLC, phospholipase C; NF-κB, nuclear factor-kappa B; AP-1, activator protein 1; iNOS, inducible nitric oxide synthase; Cox-2, cycloxygenase-2; GSH, reduced glutathione;