Disease relevance of Akr1b3

• These findings indicate that AR is responsible for the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal lesions, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and neovascularization [1].
• Aldose reductase mRNA expression (a gene upregulated by medullary hyperosmolarity) increased in normal mice, but remained low in the cystic kidney, suggesting the absence of a hypertonic medullary interstitium [2].
• Aldose reductase (AR), best known as the first enzyme in the polyol pathway of sugar metabolism, has been implicated in a wide variety of physiological functions and in the etiology of diabetic complications [3].
• Aldose reductase (ALR2) is thought to be involved in the pathogenesis of various diseases associated with diabetes mellitus, such as cataract, retinopathy, neuropathy, and nephropathy [4].
• Collectively, these data provide evidence that inhibition of AR may be a significant therapeutic approach in preventing bacterial endotoxin-induced sepsis and tissue damage [5].

Psychiatry related information on Akr1b3

• The effects of dexmedetomidine, a subtype-nonselective alpha 2-AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the alpha 2C-AR gene and in their controls, but the hypothermic effect of the alpha 2-AR agonist was significantly attenuated by the receptor gene inactivation [6].

High impact information on Akr1b3

• Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis [7].
• The production of AR was highly correlated with the presence of 4-hydroxynonenal (HNE), a toxic aldehyde and downstream product of lipid peroxidation [8].
• Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis [8].
• The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat [8].
• Upregulated AR expression was limited to areas of tissue destruction in inflamed arteries, where it was detected in T cells, macrophages, and smooth muscle cells [8].

Chemical compound and disease context of Akr1b3

• METHODS AND RESULTS: We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme aldose reductase, which catalyzes the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates [9].
• Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin e2 production in human colon cancer cells [10].
• The function of the vas deferens protein is unknown; however, aldose reductase is an NADPH-dependent monomeric oxidoreductase implicated in the pathogenesis of diabetic complications [11].
• Characterization of a novel aldose reductase inhibitor, TAT, and its effects on streptozotocin-induced diabetic neuropathy in rats [12].
• Aldose reductase activity is increased in neuroblastoma cells grown in media containing 30 mM fructose and/or 30 mM glucose [13].

Biological context of Akr1b3

• Aldose reductase deficiency prevents diabetes-induced blood-retinal barrier breakdown, apoptosis, and glial reactivation in the retina of db/db mice [1].
• Differential control of murine aldose reductase and fibroblast growth factor (FGF)-regulated-1 gene expression in NIH 3T3 cells by FGF-1 treatment and hyperosmotic stress [14].
• Aldehyde reductase isozymes in the mouse: evidence for two new loci and localization of Ahr-3 on chromosome 7 [15].
• It is proposed that Ahr-1 is a product of a gene duplication event during mammalian evolution of the primordial mammalian Adh locus and that considerable divergence in catalytic properties has subsequently occurred [16].
• Biochemical genetics of aldehyde reductase in the mouse: Ahr-1--a new locus linked to the alcohol dehydrogenase gene complex on chromosome 3 [16].

Anatomical context of Akr1b3

• AR deficiency also prevented diabetes-induced reduction of platelet/endothelial cell adhesion molecule-1 expression and increased expression of vascular endothelial growth factor, which may have contributed to blood-retinal barrier breakdown [1].
• AR deficiency led to fewer retinal blood vessels with IgG leakage, suggesting that AR may contribute to blood-retinal barrier breakdown [1].
• Aldose Reductase Mediates the Lipopolysaccharide-induced Release of Inflammatory Mediators in RAW264.7 Murine Macrophages [5].
• From a mouse kidney library, we isolated aldose reductase cDNA that encodes a 316-amino-acid protein with approximately 97% identity to rat lens aldose reductase, approximately 69% identity to the mouse vas deferens protein and also approximately 69% identity to mouse fibroblast growth-factor-1-regulated protein [17].
• Characterization of the mouse aldose reductase gene and promoter in a lens epithelial cell line [18].

Associations of Akr1b3 with chemical compounds

• AHR-A2 exhibited a defined specificity toward p-nitrobenzaldehyde as substrate, whereas the other enzymes exhibited broad specificities toward various aliphatic, aromatic, and monosaccharide aldehydes [16].
• Evidence is presented for two new forms of mouse liver and kidney aldehyde reductase activity (designated AHR-3 and AHR-4) resolved using cellulose acetate electrophoresis zymogram techniques and stained by glyceraldehyde and NADPH as substrate and coenzyme, respectively [15].
• No recombinants were observed between Adh-3 (encoding alcohol dehydrogenase C2; ADH-C2) and Ahr-1 among 42 backcross animals [16].
• Using transgenic mice that overexpress aldose reductase (AR) in their lenses, we found that the flux of glucose through the polyol pathway is the major cause of hyperglycemic oxidative stress in this tissue [19].
• In renal medullary cells, AR also plays an osmoregulatory role by accumulating sorbitol to maintain the intracellular osmotic balance during antidiuresis [20].

Physical interactions of Akr1b3

• The FR-1 ternary complex structure indicates that it uses the same general catalytic mechanism as aldose reductase and other members of the family whose structures have been determined [21].

Regulatory relationships of Akr1b3

• Steroidogenic factor-1 controls the aldose reductase akr1b7 gene promoter in transgenic mice through an atypical binding site [22].
• These data suggest that fructose may be activating or increasing sorbinil-resistant aldose reductase activity as well as partially blocking sorbitol dehydrogenase activity [13].

Other interactions of Akr1b3

• The results of the present study show that pharmacological inhibition of aldose reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-kappaB and the release of tumor necrosis factor-alpha from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells [9].
• Herein, we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR; AKR1B3) modulates NF-kappaB-dependent activation of inflammatory cytokines and chemokines in mouse serum, liver, heart, and spleen [5].
• Aldose reductase-deficient mice develop nephrogenic diabetes insipidus [4].
• Sequential expression of NKCC2, TonEBP, aldose reductase, and urea transporter-A in developing mouse kidney [23].
• Aac11 apoptosis inhibitor, aldose reductase, GalNAc transferase, TCP-1 chaperonin gene, and mouse mitochondrial gene, were downregulated in vSMCs treated with BaP [24].

Analytical, diagnostic and therapeutic context of Akr1b3

• Gel filtration analyses demonstrated that AHR-A2 and HDH-A had native molecular weights of approximately 80,000 and 32,000, respectively [16].
• Transient transfection of chloramphenicol acetyltransferase reporter constructs containing various 5'-flanking regions of the mouse AR gene in CV1 cells led to the identification of a sequence spanning base pairs -1053 to -1040, required for an enhancer activity in hypertonic compared with isotonic cell culture conditions [20].
• METHODS: The mouse AR gene structure was determined by DNA sequencing, and its chromosomal localization was determined by fluorescent in situ hybridization [18].
• On the other hand, inhibition of AR during the post-ischemic reperfusion phase did not affect cardiac performance and ATP content, but it significantly attenuated creatine kinase release and the level of thiobarbiturate-reactive substances in transgenic mouse hearts [25].
• Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism [25].

References