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Gene Review

Akr1b8  -  aldo-keto reductase family 1, member B8

Mus musculus

Synonyms: AR, Aldehyde reductase, Aldose reductase-related protein 2, FR-1, Fgfrp, ...
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Disease relevance of Akr1b8


High impact information on Akr1b8


Biological context of Akr1b8

  • Two distinct murine genes have been identified that are predicted to encode proteins with significant amino acid sequence identity with mouse AR: mouse vas deferens protein and fibroblast growth factor (FGF)-regulated-1 protein (FR-1) [7].
  • Therefore these structurally related enzymes may have at least some distinct cellular functions; for example, although both AR and FR-1 activity may be important for the metabolic changes associated with cellular proliferation, AR may be the primary aldo-keto reductase involved in cellular osmoregulation [7].
  • 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 [8].
  • 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 [9].
  • FR-1 folds into a (beta/alpha)8 barrel with an active site characterized by a preponderance of hydrophobic residues residing in a deep oblong cavity at the C-terminal end of the beta-barrel [10].

Anatomical context of Akr1b8

  • FR-1 mRNA is detectable in a number of mouse tissues but is most abundant in newborn liver and in adult intestine, ovary, and testis [11].
  • FGF-2 or phorbol ester treatment can also increase FR-1 mRNA levels; in contrast, whole blood serum or individual growth factors present in serum have only minimal effects on FR-1 mRNA expression [11].
  • Here we report that the AR and FR-1 genes are differentially regulated in NIH 3T3 fibroblasts [7].
  • Finally, when NIH 3T3 cells are grown in hypertonic medium, AR mRNA levels are significantly increased whereas FR-1 mRNA levels are only slightly up-regulated [7].
  • The localization of both MVDP and FR-1 transcripts in the adrenal cortex by in situ hybridization led to the speculation that these two AR-like proteins could be related to hormone production [8].

Associations of Akr1b8 with chemical compounds

  • Treatment of neonatal animals with furosemide dramatically reduced expression of TonEBP, AR, and UT-A1 [12].
  • We have determined the 1.7 A resolution structure of the FR-1 in a ternary complex with NADPH and zopolrestat, a potent aldose reductase inhibitor [10].
  • When inhibitors of AR were applied during the pre-ischemic phase, they significantly improved deranged cardiac function, creatine kinase release, and ATP content [1].
  • 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 [2].
  • The diabetic AR(-/-) mice also excreted less 8-hydroxy-2'-deoxyguanosine in urine than diabetic AR(+/+) mice [2].

Physical interactions of Akr1b8

  • 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 [10].

Regulatory relationships of Akr1b8


Analytical, diagnostic and therapeutic context of Akr1b8

  • FGF-1 treatment also increases FR-1 protein expression, as determined by Western-blot analysis using FR-1-specific polyclonal antiserum [7].
  • 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].
  • The enzyme aldose reductase (AR) has been implicated in the pathogenesis of some of these diseases and inhibitors of AR (ARIs) were effective in preventing some of the diabetic complications in animal models [13].
  • MATERIALS AND METHODS: Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days [14].
  • The VH and VL regions were amplified from cDNA by PCR using 5' end FR1 and 3' end constant region primers, and then sequenced [15].


  1. Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism. Iwata, K., Matsuno, K., Nishinaka, T., Persson, C., Yabe-Nishimura, C. J. Pharmacol. Sci. (2006) [Pubmed]
  2. Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage. Ho, E.C., Lam, K.S., Chen, Y.S., Yip, J.C., Arvindakshan, M., Yamagishi, S., Yagihashi, S., Oates, P.J., Ellery, C.A., Chung, S.S., Chung, S.K. Diabetes (2006) [Pubmed]
  3. Cataracts in experimentally diabetic mouse: morphological and apoptotic changes. Hegde, K.R., Varma, S.D. Diabetes, obesity & metabolism. (2005) [Pubmed]
  4. Independently derived murine glomerular immune deposit-forming anti-DNA antibodies are encoded by near-identical VH gene sequences. Katz, M.S., Foster, M.H., Madaio, M.P. J. Clin. Invest. (1993) [Pubmed]
  5. Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain. Ding, Z., Gillespie, L.L., Paterno, G.D. Mol. Cell. Biol. (2003) [Pubmed]
  6. Secreted FGFR3, but not FGFR1, inhibits lens fiber differentiation. Govindarajan, V., Overbeek, P.A. Development (2001) [Pubmed]
  7. 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. Hsu, D.K., Guo, Y., Peifley, K.A., Winkles, J.A. Biochem. J. (1997) [Pubmed]
  8. Tissue-specific expression of two aldose reductase-like genes in mice: abundant expression of mouse vas deferens protein and fibroblast growth factor-regulated protein in the adrenal gland. Lau, E.T., Cao, D., Lin, C., Chung, S.K., Chung, S.S. Biochem. J. (1995) [Pubmed]
  9. Comparisons of genomic structures and chromosomal locations of the mouse aldose reductase and aldose reductase-like genes. Ho, H.T., Jenkins, N.A., Copeland, N.G., Gilbert, D.J., Winkles, J.A., Louie, H.W., Lee, F.K., Chung, S.S., Chung, S.K. Eur. J. Biochem. (1999) [Pubmed]
  10. 1.7 A structure of FR-1, a fibroblast growth factor-induced member of the aldo-keto reductase family, complexed with coenzyme and inhibitor. Wilson, D.K., Nakano, T., Petrash, J.M., Quiocho, F.A. Biochemistry (1995) [Pubmed]
  11. A delayed-early gene activated by fibroblast growth factor-1 encodes a protein related to aldose reductase. Donohue, P.J., Alberts, G.F., Hampton, B.S., Winkles, J.A. J. Biol. Chem. (1994) [Pubmed]
  12. Sequential expression of NKCC2, TonEBP, aldose reductase, and urea transporter-A in developing mouse kidney. Lee, H.W., Kim, W.Y., Song, H.K., Yang, C.W., Han, K.H., Kwon, H.M., Kim, J. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  13. Genetic analysis of aldose reductase in diabetic complications. Chung, S.S., Chung, S.K. Current medicinal chemistry. (2003) [Pubmed]
  14. A reliable model of intravenous MDMA self-administration in naïve mice. Trigo, J.M., Panayi, F., Soria, G., Maldonado, R., Robledo, P. Psychopharmacology (Berl.) (2006) [Pubmed]
  15. Bacterial single-chain antibody fragments, specific for carcinoembryonic antigen. Ayala, M., Dueñas, M., Santos, A., Vázquez, J., Menéndez, A., Silva, A., Gavilondo, J.V. BioTechniques (1992) [Pubmed]
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