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Gene Review

NOX4  -  NADPH oxidase 4

Homo sapiens

Synonyms: KOX, KOX-1, Kidney oxidase-1, Kidney superoxide-producing NADPH oxidase, RENOX, ...
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Disease relevance of NOX4

  • Elevated NOX4 mRNA levels were detectable as early as 24 h after the onset of ischemia and persisted throughout the 30 days of follow-up period, reaching a maximum between days 7 and 15 [1].
  • Melanoma proliferation was reduced by NAD(P)H oxidase inhibitors and by transfection of antisense but not sense oligonucleotides for p22(phox) and NOX4 [2].
  • The present study was carried out to examine the expression of NOX4, one of the new NADPH oxidase isoforms in a mouse model of focal permanent brain ischemia [1].
  • In HEK293 cells expressing NOX4 endogenously, the activity of expressed TASK-1 was moderately inhibited by hypoxia, and this oxygen response was significantly augmented by NOX4 [3].
  • Here, we show that both a flavoprotein inhibitor, diphenylene iodonium (DPI), and small interfering RNAs designed to target Nox4 mRNA (siNox4RNAs) inhibited superoxide production in PANC-1 pancreatic cancer cells, and depletion of ROS by DPI or siNox4RNAs induced apoptosis [4].

High impact information on NOX4

  • Identification of renox, an NAD(P)H oxidase in kidney [5].
  • Our data suggest that Renox, as a renal source of reactive oxygen species, is a likely candidate for the oxygen sensor function regulating oxygen-dependent gene expression and may also have a role in the development of inflammatory processes in the kidney [5].
  • NIH 3T3 fibroblasts overexpressing transfected Renox show increased production of superoxide and develop signs of cellular senescence [5].
  • In situ RNA hybridization revealed that renox is highly expressed at the site of erythropoietin production in the renal cortex, showing the greatest accumulation of renox mRNA in proximal convoluted tubule epithelial cells [5].
  • Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade [6].

Chemical compound and disease context of NOX4


Biological context of NOX4

  • The human NOX4 gene, comprising 18 exons, is located on chromosome 11q14.2-q21, and its expression is almost exclusively restricted to adult and fetal kidneys [10].
  • The NOX4 protein of 578 amino acids exhibits 39% identity to gp91(phox) with special conservation in membrane-spanning regions and binding sites for heme, FAD, and NAD(P)H, indicative of its function as a superoxide-producing NAD(P)H oxidase [10].
  • The present findings thus suggest that the novel NAD(P)H oxidase NOX4 may serve as an oxygen sensor and/or a regulator of cell growth in kidney [10].
  • NOX4, widely expressed in kidney, vascular cells, osteoclasts etc.; it might be a constitutively active enzyme, regulated on the level of gene expression but its precise physiological function remains unknown [11].
  • Furthermore, transient transfection of endothelial cells with Nox4 siRNA led to a decrease in migration and adhesion of monocytes in response to LPS by 36% and 52%, respectively [12].

Anatomical context of NOX4


Associations of NOX4 with chemical compounds

  • Here we describe the cloning of human cDNA that encodes a novel NAD(P)H oxidase, designated NOX4 [10].
  • The membrane fraction of kidney-derived human embryonic kidney (HEK) 293 cells, expressing NOX4, exhibits NADH- and NADPH-dependent superoxide-producing activities, both of which are inhibited by diphenylene iodonium, an agent known to block oxygen sensing, and decreased in cells expressing antisense NOX4 mRNA [10].
  • Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells [12].
  • Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA [16].
  • We further showed that the lower-level tyrosine phosphorylation in response to growth factors results from the downregulation of an NADPH oxidase, Nox4, which in turn results in the reduction of ROS generation [17].

Physical interactions of NOX4

  • Yeast two hybrid and GST pull-down assays indicated that the COOH-terminal region of Nox4 interacted with the cytoplasmic tail of TLR4 [18].

Regulatory relationships of NOX4


Other interactions of NOX4

  • METHODS AND RESULTS: Yeast two-hybrid and glutathione-S-transferase pull-down assays indicated that the cytosolic Toll/IL-1R region of Toll-like receptor 4 (TLR4) (amino acids 739-769) is the responsible domain for interaction with the COOH terminal of Nox4 (amino acids 451-530) [12].
  • NOX2 and NOX4 were abundantly expressed, whereas NOX1 expression was less prominent [14].
  • In human renal cortex, high amounts of the NOX4 protein are present in distal tubular cells, which reside near erythropoietin-producing cells [10].
  • Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs [21].
  • Aortic lesions also expressed Thox1 and Nox4, and although their expression also increases with lesion severity, their expression is less frequent than that of gp91(phox) [22].

Analytical, diagnostic and therapeutic context of NOX4


  1. Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Vallet, P., Charnay, Y., Steger, K., Ogier-Denis, E., Kovari, E., Herrmann, F., Michel, J.P., Szanto, I. Neuroscience (2005) [Pubmed]
  2. An NAD(P)H oxidase regulates growth and transcription in melanoma cells. Brar, S.S., Kennedy, T.P., Sturrock, A.B., Huecksteadt, T.P., Quinn, M.T., Whorton, A.R., Hoidal, J.R. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  3. NOX4 as an oxygen sensor to regulate TASK-1 activity. Lee, Y.M., Kim, B.J., Chun, Y.S., So, I., Choi, H., Kim, M.S., Park, J.W. Cell. Signal. (2006) [Pubmed]
  4. Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Mochizuki, T., Furuta, S., Mitsushita, J., Shang, W.H., Ito, M., Yokoo, Y., Yamaura, M., Ishizone, S., Nakayama, J., Konagai, A., Hirose, K., Kiyosawa, K., Kamata, T. Oncogene (2006) [Pubmed]
  5. Identification of renox, an NAD(P)H oxidase in kidney. Geiszt, M., Kopp, J.B., Várnai, P., Leto, T.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mahadev, K., Motoshima, H., Wu, X., Ruddy, J.M., Arnold, R.S., Cheng, G., Lambeth, J.D., Goldstein, B.J. Mol. Cell. Biol. (2004) [Pubmed]
  7. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Lassègue, B., Clempus, R.E. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2003) [Pubmed]
  8. Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. Vaquero, E.C., Edderkaoui, M., Pandol, S.J., Gukovsky, I., Gukovskaya, A.S. J. Biol. Chem. (2004) [Pubmed]
  9. Suppression of oxidative stress in the endothelium and vascular wall. Jiang, F., Drummond, G.R., Dusting, G.J. Endothelium (2004) [Pubmed]
  10. A novel superoxide-producing NAD(P)H oxidase in kidney. Shiose, A., Kuroda, J., Tsuruya, K., Hirai, M., Hirakata, H., Naito, S., Hattori, M., Sakaki, Y., Sumimoto, H. J. Biol. Chem. (2001) [Pubmed]
  11. Tissue distribution and putative physiological function of NOX family NADPH oxidases. Krause, K.H. Jpn. J. Infect. Dis. (2004) [Pubmed]
  12. Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells. Park, H.S., Chun, J.N., Jung, H.Y., Choi, C., Bae, Y.S. Cardiovasc. Res. (2006) [Pubmed]
  13. Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Van Buul, J.D., Fernandez-Borja, M., Anthony, E.C., Hordijk, P.L. Antioxid. Redox Signal. (2005) [Pubmed]
  14. NOX2 and NOX4 Mediate Proliferative Response in Endothelial Cells. Petry, A., Djordjevic, T., Weitnauer, M., Kietzmann, T., Hess, J., Görlach, A. Antioxid. Redox Signal. (2006) [Pubmed]
  15. Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity. Piccoli, C., Ria, R., Scrima, R., Cela, O., D'Aprile, A., Boffoli, D., Falzetti, F., Tabilio, A., Capitanio, N. J. Biol. Chem. (2005) [Pubmed]
  16. TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. Patel, D.N., Bailey, S.R., Gresham, J.K., Schuchman, D.B., Shelhamer, J.H., Goldstein, B.J., Foxwell, B.M., Stemerman, M.B., Maranchie, J.K., Valente, A.J., Mummidi, S., Chandrasekar, B. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  17. Impaired generation of reactive oxygen species in leprechaunism through downregulation of Nox4. Park, H.S., Jin, D.K., Shin, S.M., Jang, M.K., Longo, N., Park, J.W., Bae, D.S., Bae, Y.S. Diabetes (2005) [Pubmed]
  18. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. Park, H.S., Jung, H.Y., Park, E.Y., Kim, J., Lee, W.J., Bae, Y.S. J. Immunol. (2004) [Pubmed]
  19. Reactive oxygen species production via NADPH oxidase mediates TGF-beta-induced cytoskeletal alterations in endothelial cells. Hu, T., Ramachandrarao, S.P., Siva, S., Valancius, C., Zhu, Y., Mahadev, K., Toh, I., Goldstein, B.J., Woolkalis, M., Sharma, K. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  20. EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. Carmona-Cuenca, I., Herrera, B., Ventura, J.J., Roncero, C., Fernández, M., Fabregat, I. J. Cell. Physiol. (2006) [Pubmed]
  21. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Martyn, K.D., Frederick, L.M., von Loehneysen, K., Dinauer, M.C., Knaus, U.G. Cell. Signal. (2006) [Pubmed]
  22. Cytochrome b558-dependent NAD(P)H oxidase-phox units in smooth muscle and macrophages of atherosclerotic lesions. Kalinina, N., Agrotis, A., Tararak, E., Antropova, Y., Kanellakis, P., Ilyinskaya, O., Quinn, M.T., Smirnov, V., Bobik, A. Arterioscler. Thromb. Vasc. Biol. (2002) [Pubmed]
  23. Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. Bengtsson, S.H., Gulluyan, L.M., Dusting, G.J., Drummond, G.R. Clin. Exp. Pharmacol. Physiol. (2003) [Pubmed]
  24. The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Kuroda, J., Nakagawa, K., Yamasaki, T., Nakamura, K., Takeya, R., Kuribayashi, F., Imajoh-Ohmi, S., Igarashi, K., Shibata, Y., Sueishi, K., Sumimoto, H. Genes Cells (2005) [Pubmed]
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