Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders

https://doi.org/10.1016/j.cbi.2011.02.023Get rights and content

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.

Introduction

Aldose reductase (AKR1B1, in human) that belongs to aldo-keto-reductase super family of proteins catalyzes the first and rate-limiting step of the polyol pathway of glucose metabolism. Besides reducing glucose to sorbitol, AKR1B1 reduces a wide range of aldehydes and their conjugates with glutathione [1]. Our studies also suggested a beneficial role of AKR1B1 in the detoxification of toxic lipid aldehydes generated upon oxidative stress. On the other hand, the accelerated flux of sorbitol through the polyol pathway has been implicated in the pathogenesis of the secondary diabetic complications, such as cataractogenesis, retinopathy, neuropathy, nephropathy, and cardiovascular [2], [3], [4], [5], [6], [7], [8]. Demonstration that AKR1B1 inhibitors decrease the sorbitol levels and ameliorate complications of diabetes such as cataract in experimental animals strongly supports this hypothesis [9]. Although, in experimental animals AKR1B1 inhibitors have shown potential inhibition of secondary diabetic complications, none of the AKR1B1 inhibitors have passed the phase III clinical trial for the prevention of diabetic complications such as diabetic neuropathy [10]. Since, previous studies had implicated that the major cause of diabetic complications could be osmotic stress generated by polyol flux, most studies were directed towards lowering the sorbitol levels [11], [12]. However, recent studies suggest that the increased polyol pathway could alter the NADPH/NADP ratio and attenuate the glutathione reductase (GR) and glutathione peroxidase (GPx) system thereby decreasing the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio which would cause oxidative stress, a major cause of diabetic complications [8], [13], [14]. These conclusions are strongly supported by our studies showing that sugar-induced lens opacification can be significantly prevented by antioxidants such as butylated hydroxytoluene (BHT) and Trolox without decreasing highly elevated levels of sorbitol in the lens [15], [16]. Patients with hyperglycemia and atherosclerosis have increased levels of oxidative stress-generated lipid peroxidation products, such as 4-hydroxy-trans-2-nonenal (HNE) and protein-HNE conjugates in their blood [17]. Further, oxidized lipids and lipoproteins are known to stimulate the cell proliferation/death and the antioxidants such as α-tocopherol, BHT, GSH-ester, curcumin, or polyphenols attenuate it [18], [19], [20], [21], [22], [23], [24], [25], [26]. Recently, our studies also suggested that AKR1B1, besides reducing glucose, efficiently reduces oxidative stress-generated lipid aldehydes with Km in micro molar range (10–30 μM) as compared to Km glucose (50–100 mM) [27]. These studies indicate the potential role of AKR1B1 in mediating oxidative stress signals since the lipid peroxidation-derived aldehydes (LDAs) such as HNE have been shown to regulate cell signals leading to cell growth or death. We have demonstrated that HNE signals rat aortic vascular smooth muscle cells (VSMC) proliferation which is attenuated by AKR1B1 inhibitor [28]. We have further demonstrated the mechanistic relationship between oxidant generation, lipid peroxidation, HNE formation, vascular cell cytotoxicity and vascular complications such as atherosclerosis [8].

The elevated levels of ROS during hyperglycemic and peroxidative stress and cytokine response are known to trigger the inflammatory response in the tissues by upregulating several redox-sensitive transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein (AP)-1. Modulation of NF-κB has a great significance in the mitogenic process that is mediated by the ROS. Recently, it has been reported that hyperglycemia and TNF-α activate NF-κB and cause proliferation of VSMC and apoptosis of vascular endothelial cells (VEC) [29], [30]. Since hyperglycemia activates NF-κB and cytokines such as TNF-α which besides activating NF-κB, is known to stimulate AKR1B1 gene expression, it is necessary to understand the relationship and the molecular mechanisms underlying these signals. We have investigated the mechanism(s) of cytokines- and hyperglycemia-induced NF-κB activation and proliferation/apoptosis of various cells and found that AKR1B1 is involved in the mediation of oxidation/reduction signals. These investigations are important in understanding the molecular mechanisms of various inflammatory diseases.

Section snippets

Detoxification and anti-oxidative roles of AKR1B1

The most obvious endogenous source of hydrophobic aldehydes is lipid peroxidation. It is well known that during free radical-mediated peroxidation of lipids, aldehydes are produced in large amounts [31]. Moreover, several of these aldehydes display high toxicity, and so could mediate some of the biological effects ascribed to their radical precursors. However, little is known about their metabolism and detoxification. Our and others observations have shown that AKR1B1 may represent an important

AKR1B1 mediates oxidative stress signals

Under physiological conditions, there is a balance between the generation of ROS and their detoxification by antioxidant systems. In general, oxidative stress occurs when this balance is disrupted, either directly by infectious agents or by cytokines released from inflamed cells that may lead to increased ROS generation and/or decreased antioxidant defense. Normally, ROS are involved in signal transductions which mediate some of the essential cellular functions such as host cell defense,

Diabetes

Based upon extensive experimental evidence showing that the inhibition of AKR1B1 prevents or delays hyperglycemic injury in several experimental models of diabetes, it has been suggested that AKR1B1 is one of the main mediators of such secondary diabetic complications as cataractogenesis, retinopathy, neuropathy, nephropathy, and microangiopathy [2], [3], [4], [5], [6], [7], [8]. It has been proposed that the increased flux of glucose via AKR1B1 causes osmotic and oxidative stresses, which, in

Conclusions

Recent studies demonstrate that besides reducing glucose to sorbitol, AKR1B1 efficiently reduces lipid aldehydes and their conjugates with GSH. This has opened new dimensions in understanding the detoxification of reactive aldehydes generated during lipid peroxidation. Using kinetic, structural, and physiological studies, we and others have investigated the mechanisms by which AKR1B1 selectively recognizes and catalyzes the reduction of LDA and their GSH conjugates [1], [32], [35], [37], [38].

Conflict of interest statement

None declared.

Acknowledgements

This study was supported in parts by NIH grants GM071036 and EY015891 to KVR, and CA129383, DK36118 and American Asthma Foundation Grant AAF 08-0219 to SKS, a William Bowes Scholar.

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