Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders
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.
References (120)
- et al.
Lipid peroxidation product, 4-hydroxynonenal and its conjugate with GSH are excellent substrates of bovine lens aldose reductase
Biochem. Biophys. Res. Commun.
(1995) - et al.
Alpha-tocopherol prevents apoptosis of vascular endothelial cells via a mechanism exceeding that of mere antioxidation
Eur. J. Pharmacol.
(2002) - et al.
LDL-induced cytotoxicity and its inhibition by anti-oxidant treatment in cultured human endothelial cells and fibroblasts
Atherosclerosis
(1983) - et al.
Kinetic and structural characterization of the glutathione-binding site of aldose reductase
J. Biol. Chem.
(2000) - et al.
Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth
J. Biol. Chem.
(2006) - et al.
Aldose reductase mediates the mitogenic signals of cytokines
Chem. Biol. Interact.
(2003) - et al.
Role of aldose reductase in TNF-alpha-induced apoptosis of vascular endothelial cells
Chem. Biol. Interact.
(2003) Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions
Chem. Phys. Lipids
(2009)- et al.
Metabolism of lipid peroxidation product, 4-hydroxynonenal (HNE) in rat erythrocytes: role of aldose reductase
Free Radic. Biol. Med.
(2000) - et al.
Human placental aldose reductase: role of Cys-298 in substrate and inhibitor binding
Biochim. Biophys. Acta
(1994)
Characterization of the glutathione binding site of aldose reductase
Chem. Biol. Interact.
Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in isolated perfused rat heart
J. Biol. Chem.
Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells
Atherosclerosis
The H2O2 stimulon in Saccharomyces cerevisiae
J. Biol. Chem.
Involvement of NADH/NADPH oxidase in human platelet ROS production
Thromb. Res.
Intracellular oxidation/reduction status in the regulation of transcription factors NF-kappaB and AP-1
Toxicol. Lett.
The regulation of AP-1 activity by mitogen-activated protein kinases
J. Biol. Chem.
Circulating 4-hydroxynonenal-protein thioether adducts assessed by gas chromatography-mass spectrometry are increased with disease progression and aging in spontaneously hypertensive rats
Free Radic. Biol. Med.
In vitro activation of heat shock transcription factor by 4-hydroxynonenal
Chem. Biol. Interact.
4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells
J. Hepatol.
Cellular lipid peroxidation end-products induce apoptosis in human lens epithelial cells
Free Radic. Biol. Med.
Genotoxicity of HNE
Mol. Aspects Med.
4-Hydroxy-2,3-trans-nonenal induces transcription and expression of aldose reductase
Biochem. Biophys. Res. Commun.
Role of human aldo-keto-reductase AKR1B10 in the protection against toxic aldehydes
Chem. Biol. Interact.
Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages
J. Biol. Chem.
Role of PKC-dependent pathways in HNE-induced cell protein transport and secretion
Mol. Aspects Med.
Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells
J. Biol. Chem.
Aldose reductase regulates TNF-alpha-induced PGE2 production in human colon cancer cells
Cancer Lett.
Aldose reductase regulates TNF-alpha-induced cell signaling and apoptosis in vascular endothelial cells
FEBS Lett.
The effect of non-enzymatic glycation on recombinant human aldose reductase
Diabetes Res. Clin. Pract.
Interaction between the polyol pathway and non-enzymatic glycation on aortic smooth muscle cell migration and monocyte adhesion
Life Sci.
Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway
Biochem. Biophys. Res. Commun.
Current understanding of the pathogenesis of Gram-negative shock
Infect. Dis. Clin. North Am.
Anti-inflammatory effect of aldose reductase inhibition in murine polymicrobial sepsis
Cytokine
The global burden of asthma
Chest
Diabetic cataracts: mechanisms and management
Diabetes Metab. Res. Rev.
The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient
Exp. Diabetes Res.
Aldose reductase, still a compelling target for diabetic neuropathy
Curr. Drug Targets
Aldose reductase and the role of the polyol pathway in diabetic nephropathy
Kidney Int. Suppl.
Aldose reductase in diabetic microvascular complications
Curr. Drug Targets
Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts
Cardiovasc. Diabetol.
Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options
Endocr. Rev.
Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens
Proc. Natl. Acad. Sci. U. S. A.
Recent studies of aldose reductase enzyme inhibition for diabetic complications
Curr. Med. Chem.
Aldose reductase and its inhibition in the control of diabetic complications
Ann. Clin. Lab. Sci.
Potential use of aldose reductase inhibitors to prevent diabetic complications
Clin. Pharm.
Contributions of polyol pathway to oxidative stress in diabetic cataract
FASEB J.
Contribution of polyol pathway to diabetes-induced oxidative stress
J. Am. Soc. Nephrol.
Trolox protects hyperglycemia-induced cataractogenesis in cultured rat lens
Res. Commun. Chem. Pathol. Pharmacol.
Prevention of sugar-induced cataractogenesis in rats by butylated hydroxytoluene
Diabetes
Cited by (151)
Aldose reductase is a potential therapeutic target for neurodegeneration
2024, Chemico-Biological InteractionsMonotropein induces autophagy through activation of the NRF2/PINK axis, thereby alleviating sepsis-induced colonic injury
2024, International ImmunopharmacologyAldose reductase and cancer metabolism: The master regulator in the limelight
2023, Biochemical PharmacologyRecent advances in responsive hydrogels for diabetic wound healing
2023, Materials Today BioPostbiotics as potential new therapeutic agents for metabolic disorders management
2022, Biomedicine and PharmacotherapyCurrent State and Future Perspective of Diabetic Wound Healing Treatment: Present Evidence from Clinical Trials
2024, Current Diabetes Reviews