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Structure, Regulation and Evolution of the Genes for the Renin-Angiotensin and the Kallikrein-Kinin Systems

Abstract

The renin-angiotensin and the kallikrein-kinin systems play important physiological roles including regulation of blood pressure and inflammation reactions. Our understanding of the structures, gene organizations and regulations of the enzymes and the peptide precursors in these systems has remarkably increased during the past few years. This article summarizes recent progress in the molecular and genetic studies of renin, angiotensinogen, kallikrein, and kininogens, and discusses some new aspects explored in these areas of research.

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References

  1. Ondetti, M.A. and Cushman, D.W. 1982. Enzymes of the renin-angiotensin system and their inhibitors. Ann. Rev. Biochem. 51: 238–308.

    Article  Google Scholar 

  2. Reid, I.A., Morris, B.J. and Ganong, W.F. 1978. The renin-angiotensin system. Ann. Rev. Physiol. 40: 377–410.

    Article  CAS  Google Scholar 

  3. Unger, T., Ganten, D. and Lang, R.E. 1983. Converting enzyme inhibitors: antihypertensive drugs with unexpected mechanisms. Trends Pharmacol. Sci. 4: 514–519.

    Article  CAS  Google Scholar 

  4. Rougeon, F., Chambraud, B., Foote, S., Panthier, J.-J., Nageotte, R. and Corvol, P. 1981. Molecular cloning of a mouse submaxillary gland renin cDNA fragment. Proc. Natl. Acad. Sci. USA. 78: 6367–6371.

    Article  CAS  Google Scholar 

  5. Panthier, J.-J., Foote, S., Chambraud, B., Strosberg, A.D., Corvol, P. and Rougeon, F. 1982. Complete amino acid sequence and maturation of the mouse submaxillary gland renin precursor. Nature 298: 90–92.

    Article  CAS  Google Scholar 

  6. Masuda, T., Imai, T., Fukushi, T., Sudoh, M., Hirose, S. and Murakami, K. 1982. Molecular cloning of DNA complementary to mouse submandibular gland renin mRNA. Biomed. Res. 3: 541–545.

    Article  CAS  Google Scholar 

  7. Imai, T., Miyazaki, H., Hirose, S., Hori, H., Hayashi, T., Kageyama, R., Ohkubo, H., Nakanishi, S. and Murakami, K. 1983. Cloning and sequence analysis of cDNA for human renin precursor. Proc. Natl. Acad. Sci. USA. 80: 7405–7409.

    Article  CAS  Google Scholar 

  8. Soubrier, F., Panthier, J.-J., Corvol, P. and Rougeon, F. 1983. Molecular cloning and nucleotide sequence of a human renin cDNA fragment. Nucleic Acids. Res. 11: 7181–7190.

    Article  CAS  Google Scholar 

  9. Misono, K.S., Chang, J.-J. and Inagami, T. 1982. Amino acid sequence of mouse submaxillary gland renin. Proc. Natl. Acad. Sci. USA. 79: 4858–4862.

    Article  CAS  Google Scholar 

  10. Hirose, S., Kim, S.-J., Miyazaki, H., Park, Y.-S. and Murakami, K. 1985. In vitro biosynthesis of human renin and identification of plasma inactive renin as an activation intermediate. J. Biol. Chem. In press.

    Google Scholar 

  11. Blundell, T., Sibanda, B.L. and Pearl, L. 1983. Three-dimensional structure, specificity and catalytic mechanism of renin. Nature 304: 273–275.

    Article  CAS  Google Scholar 

  12. Murakami, K., Hirose, S., Miyazaki, H., Imai, T., Hori, H., Hayashi, T., Kageyama, R., Ohkubo, H. and Nakanishi, S. 1984. Complementary DNA sequences of renin. State of the art review. Hypertension 6: 1-95–I-100.

    Article  Google Scholar 

  13. Akahane, K., Umeyama, H., Nakagawa, S., Moriguchi, I., Hirose, S., Iizuka, K. and Murakami, K. 1985. Three-dimensional structure of human renin. Hypertension 7: 3–12.

    Article  CAS  Google Scholar 

  14. Shibanda, B., Blundell, T., Hobart, P.M., Fogliano, M., Bindra, J.S., Dominy, B.W. and Chirgwin, J.M. 1984. Computer graphics modelling of human renin—specificity, catalytic activity and intron-exon junctions. FEBS Lett. 174: 102–111.

    Article  Google Scholar 

  15. Carlson, W., Karplus, M. and Haber, E. 1985. Construction of a model for the three-dimensional structure of human renal renin. Hypertension 7: 13–26.

    Article  CAS  Google Scholar 

  16. Evin, G., Devin, J., Castro, B., Menard, J. and Corvol, P. 1984. Synthesis of peptides related to the prosegment of mouse submaxillary gland renin precursor: An approach to renin inhibitors. Proc. Natl. Acad. Sci. USA. 81: 48–52.

    Article  CAS  Google Scholar 

  17. Kim, S.-J., Hirose, S., Miyazaki, H., Ueno, N., Higashimori, K., Morinaga, S., Kimura, T., Sakakibara, S. and Murakami, K. 1985. Identification of plasma inactive renin as prorenin with a site-directed antibody. Biochem. Biophys. Res. Commun. 126: 641–645.

    Article  CAS  Google Scholar 

  18. Miyazaki, H., Fukamizu, A., Hirose, S., Hayashi, T., Hori, H., Ohkubo, H., Nakanishi, S. and Murakami, K. 1984. Structure of the human renin gene. Proc. Natl. Acad. Sci. USA. 81: 5999–6003.

    Article  CAS  Google Scholar 

  19. Hobart, P.M., Fogliano, M., O'connor, B.A., Schaefer, I.M. and Chirgwin, J.M. 1984. Human renin gene: Structure and sequence analysis. Proc. Natl. Acad. Sci. USA. 81: 5026–5030.

    Article  CAS  Google Scholar 

  20. Piccini, N., Knopf, J.L. and Gross, K.W. 1982. A DNA polymorphism, consistent with gene duplication, correlates with high renin levels in the mouse submaxillary gland. Cell 30: 205–213.

    Article  CAS  Google Scholar 

  21. Panthier, J.-J., Holm, I. and Rougeon, F. 1982. The mouse Rn locus: Sallele of the renin regulator gene results from a single structural gene duplication. EMBO J. 1: 1417–1421.

    Article  CAS  Google Scholar 

  22. Mullins, J.J., Burt, D.W., Windass, J.D., McTurk, P., George, H. and Brammar, W.J. 1982. Molecular cloning of two distinct renin genes from the DBA/2 mouse. EMBO J. 1: 1461–1466.

    Article  CAS  Google Scholar 

  23. Panthier, J.-J. and Rougeon, F. 1983. Kidney and submaxillary gland renins are encoded by two non-allelic genes in Swiss mice. EMBO J. 2: 675–678.

    Article  CAS  Google Scholar 

  24. Panthier, J.-J., Dreyfus, M., Roux, D.T-L. and Rougeon, F. 1984. Mouse kidney and submaxillary gland renin genes differ in their 5′ putative regulatory sequences. Proc. Natl. Acad. Sci. USA. 81: 5489–5493.

    Article  CAS  Google Scholar 

  25. Field, L.J., Philbrick, W.M., Howles, P.N., Dickinson, D.P., McGowan, R.A. and Gross, K.W. 1984. Expression of tissue-specific Ren-1 and Ren-2 genes of mice: Comparative analysis of 5′-proximal flanking regions. Mol. Cell. Biol. 4: 2321–2331.

    Article  CAS  Google Scholar 

  26. Burt, D.W., Reith, A.D. and Brammar, W.J. 1984. A retroviral provirus closely associated with the Ren-2 gene of DBA/2 mice. Nucleic Acid. Res. 12: 8579–8593.

    Article  CAS  Google Scholar 

  27. Ohkubo, H., Kageyama, R., Ujihara, M., Hirose, T., Inayama, S. and Nakanishi, S. 1983. Cloning and sequence analysis of cDNA for rat angiotensinogen. Proc. Natl. Acad. Sci. USA. 80: 2196–2200.

    Article  CAS  Google Scholar 

  28. Kageyama, R., Ohkubo, H. and Nakanishi, S. 1984. Primary structure of human preangiotensinogen deduced from the cloned cDNA sequence. Biochemistry 23: 3603–3609.

    Article  CAS  Google Scholar 

  29. Doolittle, R.F. 1983. Angiotensinogen is related to the antitrypsin-antithrombin-ovalbumin family. Science 222: 417–419.

    Article  CAS  Google Scholar 

  30. Leicht, M., Long, G.L., Chandra, T., Kurachi, K., Kidd, V.J., Mace, Jr., M., Davie, E.W. and Woo, S.L.C. 1982. Sequence homology and structural comparison between the chromsomal human α1-antitrypsin and chicken ovalbumin genes. Nature 297: 655–659.

    Article  CAS  Google Scholar 

  31. Tanaka, T., Ohkubo, H. and Nakanishi, S. 1984. Common structural organization of the angiotensinogen and the α1-antitrypsin genes. J. Biol. Chem. 259: 8063–8065.

    CAS  PubMed  Google Scholar 

  32. Travis, J. and Salvesen, G.S. 1983. Human plasma proteinase inhibitors, Ann. Rev. Biochem. 52: 655–709.

    Article  CAS  Google Scholar 

  33. Ohkubo, H., Nakayama, K., Tanaka, T. and Nakanishi, S. Tissue distribution of rat angiotensinogen mRNA and structural analysis of its heterogeneity. submitted.

  34. Richoux, J.P., Cordonnier, J.L., Bouhnik, J., Clauser, E., Corvol, P., Menard, J. and Grignon, G. 1983. Immunocytochemical localization of angiotensinogen in rat liver and kidney. Cell Tissue Res. 233: 439–451.

    Article  CAS  Google Scholar 

  35. Phillips, M.I. 1983. New evidence for brain angiotensin and for its role in hypertension. Fed. Proc. 42: 2667–2672.

    CAS  PubMed  Google Scholar 

  36. Kageyama, R., Ohkubo, H. and Nakanishi, S. 1985. Induction of rat liver angiotensinogen mRNA following acute inflammation. Biochem. Biophys. Res. Commun. 129: 826–832.

    Article  CAS  Google Scholar 

  37. Richards, R.I., Catanzaro, D.F., Mason, A.J., Morris, B.J., Baxter, J.D. and Shine, J. 1982. Mouse glandular kallikrein genes. Nucleotide sequence of cloned cDNA coding for a member of the kallikrein arginyl esteropeptidase group of serine proteases. J. Biol. Chem. 257: 2758–2761.

    CAS  PubMed  Google Scholar 

  38. Swift, G.H., Dagorn, J.-C., Ashley, P.L., Cummings, S.W. and MacDonald, R.J. 1982. Rat pancreatic kallikrein mRNA: Nucleotide sequence and amino acid sequence of the encoded preproenzyme. Proc. Natl. Acad. Sci. USA. 79: 7263–7267.

    Article  CAS  Google Scholar 

  39. Fukushima, D., Kitamura, N. and Nakanishi, S. Nucleotide sequence of cloned cDNA for human pancreatice kallikrein. Biochemistry. In press.

  40. Bode, W., Chen, Z. and Bartels, K. 1983. Refined 2Å X-ray crystal structure of porcine pancreatic kallikrein A, a specific trypsin-like serine proteinase. Crystallization, structure determination, crystallographic refinement, structure and its comparison with bovine trypsin. J. Mol. Biol. 164: 237–282.

    Article  CAS  Google Scholar 

  41. Chen, Z. and Bode, W. 1983. Refined 2.5Å X-ray crystal structure of the complex formed by porcine kallikrein A and the bovine pancreatic trypsin inhibitor. Crystallization, Patterson search, structure determination, refinement, structure and comparison with its components and with the bovine trypsin-pancreatic trypsin inhibitor complex. J. Mol. Biol. 164: 283–311.

    Article  CAS  Google Scholar 

  42. Mason, A.J., Evans, B.A., Cox, D.R., Shine, J. and Richards, R.I. 1983. Structure of mouse kallikrein gene family suggests a role in specific processing of biologically active peptides. Nature 303: 300–307.

    Article  CAS  Google Scholar 

  43. Iwanaga, S., Kato, H., Sugo, T., Ikari, N., Hashimoto, N. and Fujii, S. 1979. The Kallikrein-kinin system: A functional role of plasma kallikrein and kininogen in blood coagulation, p. 243–259. In: Biological Functions of Proteinases. Holzer, H. and Tschesche, H. (eds.). Springer-Verlag, Berlin.

    Chapter  Google Scholar 

  44. Nawa, H., Kitamura, N., Hirose, T., Asai, M., Inayama, S. and Nakanishi, S. 1983. Primary structures of bovine liver low molecular weight kininogen precursors and their two mRNAs. Proc. Natl. Acad. Sci. USA. 80: 90–94.

    Article  CAS  Google Scholar 

  45. Kitamura, N., Takagaki, Y., Furuto, S., Tanaka, T., Nawa, H. and Nakanishi, S. 1983. A single gene for bovine high molecular weight and low molecular weight kininogens. Nature 305: 545–549.

    Article  CAS  Google Scholar 

  46. Takagaki, Y., Kitamura, N. and Nakanishi, S. 1985. Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens—Primary structures of two human prekininogens. J. Biol. Chem. 260: 8601–8609.

    CAS  PubMed  Google Scholar 

  47. Furuto-Kato, S., Matsumoto, A., Kitamura, N. and Nakanishi, S. 1985. Primary structures of the mRNAs encoding the rat precursors for bradykinin and T-kinin—Structural relationship of kininogens with major acute phase protein and α1-cysteine proteinase inhibitor. J. Biol. Chem. In press.

    Google Scholar 

  48. Kitamura, N., Kitagawa, H., Fukushima, D., Takagaki, Y., Miyata, T. and Nakanishi, S. 1985. Structural organization of the human kininogen gene and a model for its evolution. J. Biol. Chem. 260: 8610–8617.

    CAS  PubMed  Google Scholar 

  49. Ohkubo, I., Kurachi, K., Takasawa, T., Shiokawa, H. and Sasaki, M. 1984. Isolation of a human cDNA for α2-thiol proteinase inhibitor and its identity with low molecular weight kininogen. Biochemistry 23: 5691–5697.

    Article  CAS  Google Scholar 

  50. Kageyama, R., Kitamura, N., Ohkubo, H. and Nakanishi, S. 1985. Differential expression of the multiple forms of rat prekininogen mRNAs after acute inflammation. J. Biol. Chem. In press.

    Google Scholar 

  51. Sueyoshi, T., Miyata, T., Kato, H. and Iwanaga, S. 1984. The primary structure of bovine high molecular weight kininogen: Determination of disulfide linkage sites (Japanese) Seikagaku. 56: 808.

  52. Okamoto, H. and Greenbaum, L.M. 1983. Isolation and structure of T-kinin. Biochem. Biophys. Res. Commun. 112: 701–708.

    Article  CAS  Google Scholar 

  53. Anderson, K.P., Martin, A.D. and Heath, E.C. 1984. Rat major acute-phase protein: Biosynthesis and characterization of a cDNA clone. Arch. Biochem. Biophys. 233: 624–635.

    Article  CAS  Google Scholar 

  54. Esnard, F. and Gauthier, F. 1983. Rat α1-cysteine proteinase inhibitor. An acute phase reactant identical with α1 acute phase globulin. J. Biol. Chem. 258: 12443–12447.

    CAS  PubMed  Google Scholar 

  55. Cole, T., Inglis, A., Nagashima, M. and Schreiber, G. 1985. Major acute-phase alpha(1)protein in the rat: Structure, molecular cloning, and regulation of mRNA levels. Biochem. Biophys. Res. Commun. 126: 719–724.

    Article  CAS  Google Scholar 

  56. Cole, T., Inglis, A.S., Roxburgh, C.M., Hewlett, G.J. and Schreiber, G. 1985. Major acute phase α1-protein of the rat is homologous to bovine kininogen and contains the sequence for bradykinin: its synthesis is regulated at the mRNA level. FEBS Lett. 182: 57–61.

    Article  CAS  Google Scholar 

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Nakanishi, S., Kitamura, N. & Ohkubo, H. Structure, Regulation and Evolution of the Genes for the Renin-Angiotensin and the Kallikrein-Kinin Systems. Nat Biotechnol 3, 1089–1098 (1985). https://doi.org/10.1038/nbt1285-1089

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