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Gene Review

Ren2  -  renin 2 tandem duplication of Ren1

Mus musculus

Synonyms: Angiotensinogenase, Ren, Ren-1, Ren-2, Ren-B, ...
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Disease relevance of Ren2

  • We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background [1].
  • Hypertensive transgenic rats overexpressing the Ren2 gene express anxiotic behavioral profile. Melatonin show the anti-anxiogenic effect in these TGR rats [2].
  • These studies demonstrate that, in the absence of Ren1(d), Ren2 preserves normal kidney development and prevents severe hypotension [3].
  • Chimeric genes containing the 5'-flanking regions of the mouse renin genes, Ren1 and Ren2, associated with the early region of the simian virus 40 (SV40) were constructed [4].
  • Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat [5].
  • Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene [6].

High impact information on Ren2


Chemical compound and disease context of Ren2


Biological context of Ren2


Anatomical context of Ren2

  • The two recombinant genes which contain, respectively, 0.45- and 2.5-kb the Ren1 and Ren2 5'-flanking sequences, named Ren1Tag and Ren2Tag, were microinjected into fertilized eggs [4].
  • Ren-2 is clearly expressed in kidney, SMG and testes [17].
  • Furthermore, 5'-flanking sequences of Ren-2, placed upstream of the thymidine kinase or SV40 early region promoters do not alter the activity of these promoters in three different cell lines [18].
  • It is intriguing that Ren-2, the duplicated mouse renin gene, is expressed to high levels in the male salivary gland and also contains a transposed intracisternal A-particle genome [19].
  • Organs that are involved in cardiovascular regulation, such as the adrenal gland, kidney, and brain, express the Ren-2 gene before hypertension has developed, consistent with the possibility of a causal relationship between transgene expression in these tissues and hypertension [20].

Associations of Ren2 with chemical compounds

  • Expression of the mouse renin genes (Ren1 and Ren2) in the submaxillary gland of female mice has been analyzed following administration of thyroxine (T4) or dihydrotestosterone (DHT) [15].
  • Chronic losartan treatment results in compensation via recruitment of both Ren1(d)- and Ren2-expressing cells along the preglomerular vessels [3].
  • The Ren-1 locus of mice encodes the protease renin, which with converting enzyme processes angiotensinogen to the potent vasopressor angiotensin II [21].
  • Male Ren2 (6-7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk [5].
  • Systolic blood pressures were measured in conscious male Cyp1a1-Ren2 rats (n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days [22].

Enzymatic interactions of Ren2


Regulatory relationships of Ren2


Other interactions of Ren2


Analytical, diagnostic and therapeutic context of Ren2

  • The effects of DHT and T4 were also analyzed in transgenic mice obtained by microinjection of the Ren2 gene [15].
  • Sequence analysis of a 319 bp renin cDNA recombinant isolated from a kidney library from the two-gene strain DBA/2Ha corresponds to a transcript of the Ren-1 gene [21].
  • In this study, an enzyme which specifically cleaves mouse Ren 2 prorenin at the paired basic residues has been purified from mouse submandibular gland by CM-Toyopearl chromatography, antipain-Sepharose chromatography, and isoelectric focusing [29].
  • We have used gene targeting to discover the effects of inactivating the duplicated (Ren-2) gene in strain 129 mice, and we show that mice lacking the Ren-2 gene are viable and healthy [30].
  • In this study, a direct ELISA for Ren-2 renin (SMG renin) was established by a sandwich method [31].


  1. Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats. Kantachuvesiri, S., Haley, C.S., Fleming, S., Kurian, K., Whitworth, C.E., Wenham, P., Kotelevtsev, Y., Mullins, J.J. Kidney Int. (1999) [Pubmed]
  2. Effect of melatonin on exploration and anxiety in normotensive and hypertensive rats with high activity of renin-angiotensin system. Krsková, L., Vrabcová, M., Zeman, M. Neuro. Endocrinol. Lett. (2007) [Pubmed]
  3. Ren1d and Ren2 cooperate to preserve homeostasis: evidence from mice expressing GFP in place of Ren1d. Pentz, E.S., Lopez, M.L., Kim, H.S., Carretero, O., Smithies, O., Gomez, R.A. Physiol. Genomics (2001) [Pubmed]
  4. Renin-promoter SV40 large T-antigen transgenes induce tumors irrespective of normal cellular expression of renin genes. Sola, C., Tronik, D., Dreyfus, M., Babinet, C., Rougeon, F. Oncogene Res. (1989) [Pubmed]
  5. Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat. Hayden, M.R., Chowdhury, N.A., Cooper, S.A., Whaley-Connell, A., Habibi, J., Witte, L., Wiedmeyer, C., Manrique, C.M., Lastra, G., Ferrario, C., Stump, C., Sowers, J.R. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  6. Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene. Rothermund, L., Pinto, Y.M., Vetter, R., Herfort, N., Kossmehl, P., Neumayer, H.H., Paul, M., Kreutz, R. J. Hypertens. (2001) [Pubmed]
  7. A DNA polymorphism, consistent with gene duplication, correlates with high renin levels in the mouse submaxillary gland. Piccini, N., Knopf, J.L., Gross, K.W. Cell (1982) [Pubmed]
  8. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Mullins, J.J., Peters, J., Ganten, D. Nature (1990) [Pubmed]
  9. Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. Merrill, D.C., Thompson, M.W., Carney, C.L., Granwehr, B.P., Schlager, G., Robillard, J.E., Sigmund, C.D. J. Clin. Invest. (1996) [Pubmed]
  10. Expression of the DBA/2J Ren-2 gene in the adrenal gland of transgenic mice. Mullins, J.J., Sigmund, C.D., Kane-Haas, C., Gross, K.W., McGowan, R.A. EMBO J. (1989) [Pubmed]
  11. Nifedipine, losartan and captopril effects on hyperplasia of vascular smooth muscle from Ren-2 transgenic rats. Peiró, C., Angulo, J., Regadera, J., Llergo, J.L., Sánchez-Ferrer, A., Rodríguez-Mañas, L., Sánchez-Ferrer, C.F. Eur. J. Pharmacol. (1997) [Pubmed]
  12. Angiotensin II mediates cell hypertrophy in vascular smooth muscle cultures from hypertensive Ren-2 transgenic rats by an amiloride- and furosemide-sensitive mechanism. Peiró, C., Angulo, J., Llergo, J.L., Rodríguez-Mañas, L., Marín, J., Sánchez-Ferrer, C.F. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  13. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Mifsud, S., Kelly, D.J., Qi, W., Zhang, Y., Pollock, C.A., Wilkinson-Berka, J.L., Gilbert, R.E. Nephron. Physiology [electronic resource]. (2003) [Pubmed]
  14. Dual renin gene targeting by Cre-mediated interchromosomal recombination. Matsusaka, T., Kon, V., Takaya, J., Katori, H., Chen, X., Miyazaki, J., Homma, T., Fogo, A., Ichikawa, I. Genomics (2000) [Pubmed]
  15. Thyroxine and testosterone transcriptionally regulate renin gene expression in the submaxillary gland of normal and transgenic mice carrying extra copies of the Ren2 gene. Tronik, D., Rougeon, F. FEBS Lett. (1988) [Pubmed]
  16. Kidney and submaxillary gland renins are encoded by two non-allelic genes in Swiss mice. Panthier, J.J., Rougeon, F. EMBO J. (1983) [Pubmed]
  17. Differential extra-renal expression of the mouse renin genes. Miller, C.C., Carter, A.T., Brooks, J.I., Lovell-Badge, R.H., Brammar, W.J. Nucleic Acids Res. (1989) [Pubmed]
  18. The activity of the mouse renin promoter in cells that do not normally produce renin is dependent upon the presence of a functional enhancer. Ekker, M., Sola, C., Rougeon, F. FEBS Lett. (1989) [Pubmed]
  19. The angiotensinogen gene of Swiss mice is closely linked to a retrovirus-like element. Clouston, W.M. DNA Cell Biol. (1990) [Pubmed]
  20. Ontogenetic regulation of mouse Ren-2d renin gene in transgenic hypertensive rats, TGR(mREN2)27. Zhao, Y., Bader, M., Kreutz, R., Fernandez-Alfonso, M., Zimmermann, F., Ganten, U., Metzger, R., Ganten, D., Mullins, J.J., Peters, J. Am. J. Physiol. (1993) [Pubmed]
  21. Tissue and gene specificity of mouse renin expression. Field, L.J., McGowan, R.A., Dickinson, D.P., Gross, K.W. Hypertension (1984) [Pubmed]
  22. Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats. Howard, L.L., Patterson, M.E., Mullins, J.J., Mitchell, K.D. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  23. The crystal structure of the mouse glandular kallikrein-13 (prorenin converting enzyme). Timm, D.E. Protein Sci. (1997) [Pubmed]
  24. Immunocytochemical localization of renin in kidneys and submandibular glands of SWR/J and C57BL/6J mice. Tanaka, T., Gresik, E.W., Michelakis, A.M., Barka, T. J. Histochem. Cytochem. (1980) [Pubmed]
  25. Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene. Moriguchi, A., Brosnihan, K.B., Kumagai, H., Ganten, D., Ferrario, C.M. Am. J. Physiol. (1994) [Pubmed]
  26. Ablation of renin-expressing juxtaglomerular cells results in a distinct kidney phenotype. Pentz, E.S., Moyano, M.A., Thornhill, B.A., Sequeira Lopez, M.L., Gomez, R.A. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  27. Location on chromosome 1 of Rnr, a gene that regulates renin in the submaxillary gland of the mouse. Wilson, C.M., Erdös, E.G., Wilson, J.D., Taylor, B.A. Proc. Natl. Acad. Sci. U.S.A. (1978) [Pubmed]
  28. Prorenin processing and restricted endoproteolysis by mouse tissue kallikrein family enzymes (mK1, mK9, mK13, and mK22). Kikkawa, Y., Yamanaka, N., Tada, J., Kanamori, N., Tsumura, K., Hosoi, K. Biochim. Biophys. Acta (1998) [Pubmed]
  29. A processing enzyme for prorenin in mouse submandibular gland. Purification and characterization. Kim, W.S., Hatsuzawa, K., Ishizuka, Y., Hashiba, K., Murakami, K., Nakayama, K. J. Biol. Chem. (1990) [Pubmed]
  30. Targeted inactivation of the Ren-2 gene in mice. Sharp, M.G., Fettes, D., Brooker, G., Clark, A.F., Peters, J., Fleming, S., Mullins, J.J. Hypertension (1996) [Pubmed]
  31. Ren-2 as well as Ren-1 renin exists in the kidney and plasma of a two-renin gene mouse. Suzuki, F., Yamashita, S., Ito, M., Nagata, Y., Nakamura, Y. Agric. Biol. Chem. (1990) [Pubmed]
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