Disease relevance of Akr1b4

• The RT-PCR system developed in this study may be a useful tool in ascertaining the relative contributions of AR and SDH to the metabolic derangements resulting from the acceleration of polyol pathway activity in the target organ of diabetic complications [1].
• Despite differences in the etiology of diabetes mellitus, the strain of rat and the rate of disease progression in the OLETF rat model compared with other diabetic models, the present results support the theory that the polyol pathway via AR is a factor in the development of sugar cataracts [2].
• Results demonstrate that ischemia increases myocardial aldose reductase activity and that these increases are, in part, due to activation by nitric oxide [3].
• However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase [4].
• Treatment of diabetic rats for 14 weeks with the aldose reductase inhibitor zopolrestat resulted in a significant decrease in the frequency of neuroaxonal dystrophy compared with untreated diabetics [5].

Psychiatry related information on Akr1b4

• Finally, in Brattleboro rats, urine osmolality and levels of aldose reductase and taurine cotransporter mRNA increased in response to 1 day of water deprivation, whereas sorbitol dehydrogenase mRNA was unchanged [6].
• METHODS: In the present study, adult male rats were treated with ICI 182,780 for 7 to 150 days, to evaluate the time-response effects of the treatment on the pattern of ERalpha, ERbeta and AR protein expression in the efferent ductules [7].

High impact information on Akr1b4

• Aldose reductase inhibitors firmly link defects in myo-inositol metabolism to activation of the polyol pathway in diabetes; the resulting "sorbitol-myo-inositol hypothesis" has been extended from its application to the lenses and peripheral nerves to most of the tissues involved with diabetic complications [8].
• Neither an inhibitor of the enzyme aldose reductase, present in the diet, nor diabetes mellitus, induced by streptozotocin, had any statistically significant influence on the dystrophy [9].
• A twofold thickening of capillary basement membranes of rat retinas resulting from dietary galactose was prevented by sorbinil, an inhibitor of aldose reductase [10].
• Galactosemic rats should be useful models for studying basement membrane-related complications of diabetes and for examining the potential biochemical regulation of basement membrane synthesis by aldose reductase inhibitors [10].
• Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor [10].

Chemical compound and disease context of Akr1b4

• Aldose reductase is thought to be involved in a minor pathway of glucose metabolism and in diabetic complications [11].
• Aldose reductase inhibited hearts, when subjected to ischemia/reperfusion, exhibited less ischemic injury and was associated with lower lactate/pyruvate ratios (a measure of cytosolic NADH/NAD+), greater tissue content of adenosine triphosphate, and improved cardiac function [3].
• NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction [12].
• Sorbitol, formed in the presence of aldose reductase, accumulates in the lens during hyperglycemia [13].
• Hypothermia (body temperature, 30 degrees C to 31 degrees C) did not affect IA/AR (67 +/- 3%, n = 11) in control animals but enhanced protection by 15-minute CAO (IA/AR = 22 +/- 3%, n = 8), whereas protection by 15-minute MAO (IA/AR = 44 +/- 5%, n = 11, P < .001) was minimally enhanced [14].

Biological context of Akr1b4

• Analysis of gene expression of aldose reductase and sorbitol dehydrogenase in rat Schwann cells by competitive RT-PCR method using non-homologous DNA standards [1].
• In the present study, we assessed the role of aldose reductase, the key enzyme of the polyol pathway, in cardiac myocyte apoptosis [15].
• The VSMC treated with AR inhibitors showed decreased nuclear translocation of NF-kappa B and diminished phosphorylation and proteolytic degradation of I kappa B-alpha [16].
• Inhibition of VSMC growth by AR inhibitors was not accompanied by increase in cell death or apoptosis [16].
• To better understand the role that expression of the aldose reductase-encoding gene (ALR) may play in diabetic complications, we have begun to analyze the gene and its regulatory regions, and we present here the sequence of four ALR genes in the rat [17].

Anatomical context of Akr1b4

• Fidarestat, a newly developed AR inhibitor, and N-acetylcysteine, an antioxidant, completely prevented these deleterious effects of SDH overexpression on pericytes [18].
• The induction of AR mRNA expression in the Schwann cells under hyperosmotic conditions was similarly detected by Northern blot analysis and our competitive RT-PCR method [1].
• Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells [16].
• Inhibition of AR led to a decrease in the activity of the transcription factor NF-kappa B in culture and in the neointima of rat carotid arteries after balloon injury [16].
• Long-term induction of an aldose reductase protein by basic fibroblast growth factor in rat astrocytes in vitro [11].

Associations of Akr1b4 with chemical compounds

• Acute alloxan diabetes was associated with decreased AR in small arteries, but not glomeruli [19].
• Aldose reductase induced by hyperosmotic stress mediates cardiomyocyte apoptosis: differential effects of sorbitol and mannitol [15].
• Herein we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR) inhibits NF-kappa B activation during restenosis of balloon-injured rat carotid arteries as well as VSMC proliferation due to tumor necrosis factor alpha (TNF-alpha) stimulation [16].
• Hyperosmolarity-induced cell death is sensitive to the nature of the osmolyte and requires induction of aldose reductase as well as a decrease in intracellular glutathione levels [15].
• Inhibition of AR in VSMC also prevented the activation of NF-kappa B by basic fibroblast growth factor (bFGF), angiotensin-II (Ang-II), and platelet-derived growth factor (PDGF-AB) [16].

Physical interactions of Akr1b4

• Therefore, we studied the effect of the aldose reductase inhibitor sorbinil on the axonal transport of choline acetyltransferase (ChAT) in the cholinergic neurons of the sciatic nerve of rats with short-term streptozotocin diabetes [20].

Regulatory relationships of Akr1b4

• Inhibition of aldose reductase prevented high glucose-induced DAG formation and phosphorylation of PLC-gamma1 and PLC-beta2 and -delta [21].
• Both the aldose reductase specific inhibitor (zopolrestat) or transfection with aldose reductase antisense oligonucleotide blocked the phosphorylation of JAK2, the production of ROS, and proliferation of VSMC induced by HG, but it had no effect on the Ang II-induced activation of these parameters in both NG and HG [22].

Other interactions of Akr1b4

• This study demonstrates AR and SDH in substructures of the kidney [19].
• We examined the contribution of aldose reductase, which catalyzes the first, and the rate-limiting, step of the polyol pathway of glucose metabolism, to PKC activation in vascular smooth muscle cells (VSMCs) isolated from rat aorta and exposed to high glucose in culture [21].
• Inhibition of aldose reductase prevented membrane translocation of PKC-beta2 and -delta and delayed the activation of PKC-beta1 and -epsilon, whereas membrane translocation of PKC-alpha and -gamma was not affected [21].
• Biochemically, there was elevation of gamma-glutamyl transferase, a decrease in sorbitol levels at 3 h and a decrease in the activity of aldose reductase at 6 h, in the testes of treated rats [23].
• Insulin and aldose reductase inhibitors can prevent excess polyol pathway flux, and hence these agents may prevent NCV deficits by preventing p38 MAP kinase activation [24].

Analytical, diagnostic and therapeutic context of Akr1b4

• Nonradioactive in situ hybridization studies on sections from formalin-fixed and paraffin-embedded, normally concentrating kidneys showed strong expression of BGT, SMIT, and AR mRNAs in interstitial and collecting duct cells of the papilla, whereas expression of SDH mRNA was much weaker in both cell types [25].
• The enzymatic activities, expression, and localization of AR and SDH were studied in reproductive tracts and spermatozoa of male rats by immunohistochemistry, Western blotting, and enzyme assays [26].
• Second, in rats fed a low-protein diet for 3 wk, aldose reductase mRNA increased two-fold, whereas sorbitol dehydrogenase and taurine cotransporter mRNA were unchanged [6].
• Oral administration of tolrestat, a structurally novel aldose reductase inhibitor (n = 8; 20 mg/kg twice daily 1 wk before and 4 wk after STZ injection), prevented the diabetes-induced increase in distal nerve transmission time [27].
• Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat [28].

References