Disease relevance of Akr1b7

• These results suggest a dual role of AR in ischemia-reperfusion injury [1].
• Inhibition of AR during ischemia preserved generation of ATP via glycolysis, whereas inhibition during the reperfusion phase reduced myocardial injury by attenuating oxidative stress elicited by ischemic insult and reoxygenation [1].
• Aldose reductase (AR) has been implicated in the pathogenesis of diabetic complications, although the clinical efficacy of AR inhibitors has not been clearly proven [1].
• Inhibition of aldose reductase (AR; EC. 1.1.1.21.) by sorbinil or by antisense ablation prevented fibroblast growth factor-induced and platelet-derived growth factor-induced up-regulation of PGE(2) synthesis in human colon cancer cells, Caco-2 [2].
• More importantly, in vivo studies showed that administration of AR-small interfering RNA (siRNA), but not control siRNA, to nude mice bearing SW480 human colon adenocarcinoma cells completely arrested tumor progression [2].

Psychiatry related information on Akr1b7

• 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 [3].
• These results suggest that androgens may interact with either AR or PR, and perhaps both receptors, in E2 + TP-induced mammary glands and the induced tumors to effect the reduction in latency period, enhance tumor size, and increase incidence to 100% [4].

High impact information on Akr1b7

• Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR [5].
• In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-alpha and estren-beta) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR) [5].
• Sexually dimorphic behaviors are likely to involve neural pathways that express the androgen receptor (AR) [6].
• Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene [7].
• The results provide clear in vivo evidence that androgen/AR signaling in Sertoli cells plays a direct important role in spermatogenesis and in Leydig cells plays an autocrine regulatory role to modulate Leydig cell steroidogenic function [8].

Chemical compound and disease context of Akr1b7

• In cells stably transfected with MVDP antisense cDNA, NADH-linked ICR activity was abolished even in the presence of forskolin, and the isocaproaldehyde toxicity was increased compared with that of intact Y1 cells, as measured by isocaproaldehyde LD(50) [9].
• Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage [10].
• In Y1 cells transfected with MVDP antisense cDNA, forskolin-induced toxicity was abolished by aminoglutethimide [9].
• Recent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies that reduce circulating androgen ligands to castrate levels and/or block ligand binding [11].
• It is not affected by the AR blockers cyproterone and flutamide, whereas it is completely inhibited by the phospholipase C inhibitor U-73122 and pertussis toxin [12].

Biological context of Akr1b7

• The major gene expression pattern for FR-1 was slightly different from that of MVDP, with the highest levels of mRNA detected in testis, heart, adrenal gland, and ovary; less was found in the lung and it was barely detectable in eye, intestine, liver and seminal vesicle tissue [13].
• The closely related genes Fgfrp and Avdp were also mapped in this region of the chromosome, suggesting that these three genes may have arisen by a gene duplication event [14].
• Inhibition of AR prevented growth factor-induced COX-2 activity, protein, and mRNA and significantly decreased activation of nuclear factor-kappaB and protein kinase C (PKC) and phosphorylation of PKC-beta2 as well as progression of Caco-2 cell growth but had no effect on COX-1 activity [2].
• Cell cycle analysis suggests that inhibition of AR prevents growth factor-induced proliferation of Caco-2 cells at S phase [2].
• To better understand androgenregulated MVDP gene expression, the location and sequences of androgen response elements (AREs) in the 5'-flanking DNA were determined [15].

Anatomical context of Akr1b7

• Contrary to previous reports, MVDP was detected in a variety of tissues besides the vas deferens [13].
• High levels of MVDP mRNA were found in the adrenal glands, and low levels of expression were detected in eye, intestine, seminal vesicle, kidney, liver, testis and lung [13].
• The structural abnormalities observed in the sural nerve of diabetic AR(+/+) mice were less severe in the diabetic AR(-/-) mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions [10].
• Sorbitol levels in the sciatic nerves of diabetic AR(+/+) mice were increased significantly, whereas sorbitol levels in the diabetic AR(-/-) mice were significantly lower than those in diabetic AR(+/+) mice [10].
• In this study, we report that ligand-bound AR, but not ligand-bound ER, directly suppressed activity of the bovine LHbeta promoter when examined in a gonadotrope-derived cell line [16].

Associations of Akr1b7 with chemical compounds

• In steroidogenic organs, AKR1B7/MVDP scavenges isocaproaldehyde produced from the cholesterol side-chain cleavage reaction [17].
• Treatment of neonatal animals with furosemide dramatically reduced expression of TonEBP, AR, and UT-A1 [18].
• When inhibitors of AR were applied during the pre-ischemic phase, they significantly improved deranged cardiac function, creatine kinase release, and ATP content [1].
• AR besides reducing aldo-sugars efficiently reduces toxic lipid aldehydes and their conjugates with glutathione [2].
• For MVDP, isocaproaldehyde, a product of side-chain cleavage of cholesterol generated during steroidogenesis, is the best natural substrate identified so far [9].

Regulatory relationships of Akr1b7

• We show that in adrenals, the pituitary hormone ACTH regulates MVDP gene expression in a coordinate fashion with steroidogenic genes [19].
• Furthermore, we report that MVDP gene regulation is impaired in stably transfected Y1 clones expressing DAX-1 [19].

Other interactions of Akr1b7

• Akr1b7/mvdp is responsive to ACTH in adrenals and to androgens in vas deferens [17].
• Thus, in adrenocortical cells, both SF-1 and NF1 are required for high expression of the MVDP promoter while Sp1 and C/EBPss functionally interact in an additive manner to mediate cAMP-dependent regulation [19].
• The distal response element does not bind AR, but AR reduces Sp1 binding to this region [20].
• The MVDP (mouse vas deferens protein) gene encodes an aldose reductase-like protein (AKR1B7) that is responsible for detoxifying isocaproaldehyde generated by steroidogenesis [19].
• Focusing on mitogenic effects, we demonstrate that both natural androgen receptor (AR) agonists, testosterone and DHT, dose-dependently augmented the mitogenic activity of DO or GDF9 [21].

Analytical, diagnostic and therapeutic context of Akr1b7

• 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 [1].
• In adrenocortical cell cultures, hormonal regulation of MVDP gene occurs through the cAMP pathway [19].
• Steady-state levels of MVDP mRNA are decreased by approximately 42% 3 days after castration but a significant hybridization signal is still observed even 50 days after castration [22].
• Northern blot analysis revealed that these cells only express MVDP mRNA in the presence of androgens [23].
• Using in situ hybridization we have identified the epithelial cells of the vas deferens as the site of synthesis of MVDP mRNA [22].

References