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Gene Review

Nat2  -  N-acetyltransferase 2 (arylamine N...

Rattus norvegicus

Synonyms: AT-2, Aac2, Arylamide acetylase 2, Arylamine N-acetyltransferase 2, N-acetyltransferase type 2, ...
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Disease relevance of Nat2

  • We previously reported an association between the N-acetyltransferase 2 (NAT2) slow acetylator status and Parkinson's disease (PD) [1].
  • The cardioprotective effects of rosiglitazone against myocardial ischemia-reperfusion injury are independent of its insulin-sensitizing properties and are associated with significant overexpression of AT2 receptors along with inhibition of p42/44 MAPK [2].
  • Recent studies have pointed out the differential role of angiotensin II (Ang II) receptor subtypes, AT1 and AT2, in cardiac hypertrophy and fibrosis during pathological cardiac growth [3].
  • Genes for the 290 amino acid, 33-34 kDa cytosolic acetyltransferases (NAT1* and NAT2*) from rat and hamster were cloned and expressed in Escherichia coli [4].
  • Recent evidence shows that reexpression and upregulation of angiotensin II (ANG II) type 2 (AT2) receptor in adult tissues occur during pathological conditions such as tissue hyperplasia, inflammation, and remodeling [5].

High impact information on Nat2

  • Angiotensin II interacts with two pharmacologically distinct subtypes of cell-surface receptors, AT1 and AT2 [6].
  • The neuronal expression of AT1A and AT2 receptors was demonstrated in the subfornical organ, the hypothalamus, and the lateral septum [7].
  • Chronic blockade of AT2 receptors in Ang II-induced hypertensive rats had no effect on arterial pressure, but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vasotrophic effects of Ang II are at least partially mediated via AT2 subtype receptors [8].
  • Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension [8].
  • When AT2 cells in hypoxia are exposed to carbon monoxide, mRNA II is suppressed suggesting that a heme-binding protein (responsive to oxygen) may suppress mRNA II expression and may be responsible for the decrease in lung mRNA II seen after birth [9].

Chemical compound and disease context of Nat2

  • In this study, we demonstrate that chronic in vivo estrogen treatment, which induces pituitary hyperplasia, enhances local AT2 expression (measured by Western blot and RT-PCR) concomitantly with downregulation of ANG II type 1 (AT1) receptors [5].
  • AT2 blockade for 4 days with PD123319 or beta-receptor blockade with propranolol for 3 weeks did not alter heart/body weights [10].
  • We investigated the haemodynamic parameters and the regulation of cardiac mRNA levels of the angiotensin receptor subtypes, AT1 and AT2, by the AT,-receptor antagonist losartan in rat heart during the acute phase of myocardial infarction [11].
  • In Lyon hypertensive (LH) rats, a model of low-renin genetic hypertension, we investigated adrenal sensitivity to angiotensin II in terms of angiotensin II receptor (AT1 and AT2 receptors) regulation, morphological changes, and aldosterone and corticosterone secretion [12].
  • Because the alveolar type 2 (AT2) cells participate in active Na(+) transport, we studied whether aldosterone regulates the Na,K-ATPase in rat AT2 cells and whether aldosterone delivered by aerosols to spontaneously breathing rats affects edema clearance in a model of isolated-perfused lungs [13].

Biological context of Nat2

  • To further investigate the down modulation of this gene, we studied its expression in AT-2 (anaplastic, nonmetastasizing tumor) and lines derived therefrom that exhibited a high metastatic potential after transfection with the v-Ha-ras oncogene [14].
  • In contrast, the relative binding potencies for the other (AT2) population of binding sites were CGP 42112A greater than PD 123177 much greater than Dup 753 [15].
  • In contrast, AT2 gene expression was increased in both ventricles of senescent rats (4.2- and 2.8-fold in the left and right ventricles, respectively) [3].
  • Both AT1 and AT2 receptors were present in the rat heart by late gestation and could, therefore, mediate the effects of angiotensin II on early cardiac growth and development [16].
  • The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats [17].

Anatomical context of Nat2

  • Thus, AT1 and AT2 receptors are present in rat ventricular myocardium, and their expression is developmentally regulated and upregulated in response to hypertrophic change [18].
  • The proportion of AT1 and AT2 subtypes in the specific Ang II binding in ventricular membranes prepared from normal adult rats was nearly equal [18].
  • Neurons cultured from neonatal rat hypothalamus and brainstem contain many angiotensin II (Ang II) type 2 (AT2) receptors, and we previously determined that activation of these sites elicited a stimulation of serine/threonine phosphatase 2A (PP2A) [19].
  • These data suggest that the known effects of AII in adrenal glomerulosa cells are mediated through the AT1 receptor subtype and that the distribution and/or specificity of the AT2 receptors shows marked species variations [15].
  • In 2 weakly metastatic cell lines (AT-1 and AT-2), p9Ka transcript amounts were, respectively, 6.29 +/- 0.74 and 5.55 +/- 1.11 times that detected in the G cells [20].

Associations of Nat2 with chemical compounds

  • Importantly, myocardial AT2 mRNA and protein expression were significantly increased (by >100-fold) in the rosiglitazone-rich diet group (P < 0.05) [2].
  • We have now investigated the possible functional relevance of this association by treating Fischer 344 (F344) rapid and Wistar-Kyoto (WKY) slow NAT2 acetylator rat strains with the neurotoxin 6-hydroxydopamine (6-OHDA) [1].
  • This stimulatory effect of Ang II on Erk1 and Erk2 activities was potentiated by blockade of AT2 receptors with (S)-1-[4-(dimethylamino)-3-methylphenyl]methyl-5-(diphenylacetyl)- 4, 5,6,7-tetrahydro-1H-imidazo[4,5-C]pyridine-6-carboxylic acid (PD 123319, 1 microM) [19].
  • The selective AT-2 displacers CGP 42112 A and/or PD 123177 competed with high affinity with AT bound to most receptors located in skeletal muscle, skin, diaphragm, bronchi, and stomach, and these receptors are classified as AT-2 receptors [21].
  • The temporal pattern of expression of binding for both receptor subtypes suggests that while AT2 receptors may be involved in cell proliferation and early differentiation of the nephron, AT1 receptors have a dual role, early in nephron differentiation and later in development in renal function [22].

Physical interactions of Nat2


Other interactions of Nat2

  • Cloning, sequencing and expression of NAT1 and NAT2 encoding genes from rapid and slow acetylator inbred rats [24].
  • In the genetically manipulated metastasizing tumor sublines, fibronectin mRNA levels were approximately 4- to 8-fold lowered compared to the nonmetastasizing parental AT-2 line [14].

Analytical, diagnostic and therapeutic context of Nat2

  • SDS-PAGE/Western blot analysis of the recombinant acetyltransferases gave apparent relative molecular weights (MWr) of approximately 31 kDa for both NAT1s and rat NAT2 and approximately 29 kDa for hamster NAT2 [4].
  • Radioactively labeled cRNA probes were used for in situ hybridization histochemistry to establish a detailed map of the sites of expression of the recently cloned angiotensin II, type 2 (AT2) receptor mRNA in the adult rat brain [25].
  • Angiotensin II (ANG II) receptor subtypes (AT1, displaced by losartan, and AT2, displaced by CGP 42112A) were characterized by quantitative autoradiography after incubation with the ANG II agonist [125I]Sar1-ANG II, in specific brain nuclei of 19-day-old rat embryos [26].
  • ABP, HR, and renal SNA responses to PVN microinjection of bicuculline methobromide (BIC; 0.1 nmol) were recorded before and after microinjection of vehicle (saline); losartan (or L-158809), to block local AT1 receptors; or PD123319, to block AT2 receptors [27].
  • Recently developed antisera selective for angiotensin Type 2 (AT2) receptors were used to localize AT2 receptors in rat brain by immunohistochemistry [28].


  1. Slow N-acetyltransferase 2 status leads to enhanced intrastriatal dopamine depletion in 6-hydroxydopamine-lesioned rats. Grundmann, M., Earl, C.D., Sautter, J., Henze, C., Oertel, W.H., Bandmann, O. Exp. Neurol. (2004) [Pubmed]
  2. Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK. Molavi, B., Chen, J., Mehta, J.L. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  3. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Heymes, C., Silvestre, J.S., Llorens-Cortes, C., Chevalier, B., Marotte, F., Levy, B.I., Swynghedauw, B., Samuel, J.L. Endocrinology (1998) [Pubmed]
  4. Recombinant rat and hamster N-acetyltransferases-1 and -2: relative rates of N-acetylation of arylamines and N,O-acyltransfer with arylhydroxamic acids. Jones, R.F., Land, S.J., King, C.M. Carcinogenesis (1996) [Pubmed]
  5. Upregulation of angiotensin II type 2 receptor expression in estrogen-induced pituitary hyperplasia. Suarez, C., Díaz-Torga, G., González-Iglesias, A., Cristina, C., Becu-Villalobos, D. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  6. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Murphy, T.J., Alexander, R.W., Griendling, K.K., Runge, M.S., Bernstein, K.E. Nature (1991) [Pubmed]
  7. Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Lenkei, Z., Palkovits, M., Corvol, P., Llorens-Cortès, C. Frontiers in neuroendocrinology. (1997) [Pubmed]
  8. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. Levy, B.I., Benessiano, J., Henrion, D., Caputo, L., Heymes, C., Duriez, M., Poitevin, P., Samuel, J.L. J. Clin. Invest. (1996) [Pubmed]
  9. Three alternative promoters of the rat gamma-glutamyl transferase gene are active in developing lung and are differentially regulated by oxygen after birth. Joyce-Brady, M., Oakes, S.M., Wuthrich, D., Laperche, Y. J. Clin. Invest. (1996) [Pubmed]
  10. Developmental regulation of angiotensin type 1 and 2 receptor gene expression and heart growth. Everett, A.D., Fisher, A., Tufro-McReddie, A., Harris, M. J. Mol. Cell. Cardiol. (1997) [Pubmed]
  11. Effects of losartan on haemodynamic parameters and angiotensin receptor mRNA levels in rat heart after myocardial infarction. Zhu, Y.Z., Zhu, Y.C., Li, J., Schäfer, H., Schmidt, W., Yao, T., Unger, T. Journal of the renin-angiotensin-aldosterone system : JRAAS. (2000) [Pubmed]
  12. Hypersensitivity of the adrenal cortex to trophic and secretory effects of angiotensin II in Lyon genetically-hypertensive rats. Aguilar, F., Lo, M., Claustrat, B., Saez, J.M., Sassard, J., Li, J.Y. Hypertension (2004) [Pubmed]
  13. Aldosterone regulates Na,K-ATPase and increases lung edema clearance in rats. Olivera, W.G., Ciccolella, D.E., Barquin, N., Ridge, K.M., Rutschman, D.H., Yeates, D.B., Sznajder, J.I. Am. J. Respir. Crit. Care Med. (2000) [Pubmed]
  14. Down modulation of fibronectin messenger RNA in metastasizing rat prostatic cancer cells revealed by differential hybridization analysis. Schalken, J.A., Ebeling, S.B., Isaacs, J.T., Treiger, B., Bussemakers, M.J., de Jong, M.E., Van de Ven, W.J. Cancer Res. (1988) [Pubmed]
  15. Angiotensin II receptor subtypes and biological responses in the adrenal cortex and medulla. Balla, T., Baukal, A.J., Eng, S., Catt, K.J. Mol. Pharmacol. (1991) [Pubmed]
  16. Quantification and localisation of angiotensin II receptors and angiotensin converting enzyme in the developing rat heart. Hunt, R.A., Ciuffo, G.M., Saavedra, J.M., Tucker, D.C. Cardiovasc. Res. (1995) [Pubmed]
  17. Diphenylpropionic acids as new AT1 selective angiotensin II antagonists. Almansa, C., Gómez, L.A., Cavalcanti, F.L., de Arriba, A.F., Rodríguez, R., Carceller, E., García-Rafanell, J., Forn, J. J. Med. Chem. (1996) [Pubmed]
  18. Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy. Suzuki, J., Matsubara, H., Urakami, M., Inada, M. Circ. Res. (1993) [Pubmed]
  19. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors. Huang, X.C., Richards, E.M., Sumners, C. J. Biol. Chem. (1996) [Pubmed]
  20. Elevated expression of calcium-binding protein p9Ka is associated with increasing malignant characteristics of rat prostate carcinoma cells. Ke, Y., Jing, C., Barraclough, R., Smith, P., Davies, M.P., Foster, C.S. Int. J. Cancer (1997) [Pubmed]
  21. Angiotensin-II receptor subtypes in fetal tissue of the rat: autoradiography, guanine nucleotide sensitivity, and association with phosphoinositide hydrolysis. Tsutsumi, K., Strömberg, C., Viswanathan, M., Saavedra, J.M. Endocrinology (1991) [Pubmed]
  22. Developmental changes in angiotensin II receptor subtypes and AT1 receptor mRNA in rat kidney. Aguilera, G., Kapur, S., Feuillan, P., Sunar-Akbasak, B., Bathia, A.J. Kidney Int. (1994) [Pubmed]
  23. Angiotensin II receptor subtypes in rat brain and peripheral tissues. Song, K., Zhuo, J., Allen, A.M., Paxinos, G., Mendelsohn, F.A. Cardiology (1991) [Pubmed]
  24. Cloning, sequencing and expression of NAT1 and NAT2 encoding genes from rapid and slow acetylator inbred rats. Doll, M.A., Hein, D.W. Pharmacogenetics (1995) [Pubmed]
  25. Distribution of angiotensin II type-2 receptor (AT2) mRNA expression in the adult rat brain. Lenkei, Z., Palkovits, M., Corvol, P., Llorens-Cortes, C. J. Comp. Neurol. (1996) [Pubmed]
  26. Angiotensin II receptor subtypes and angiotensin-converting enzyme in the fetal rat brain. Tsutsumi, K., Seltzer, A., Saavedra, J.M. Brain Res. (1993) [Pubmed]
  27. Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT1 receptor antagonism. Chen, Q.H., Toney, G.M. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2003) [Pubmed]
  28. Immunohistochemical mapping of angiotensin type 2 (AT2) receptors in rat brain. Reagan, L.P., Flanagan-Cato, L.M., Yee, D.K., Ma, L.Y., Sakai, R.R., Fluharty, S.J. Brain Res. (1994) [Pubmed]
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