Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 May 15;99(10):2375–2385. doi: 10.1172/JCI119419

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

C R Esther 1, E M Marino 1, T E Howard 1, A Machaud 1, P Corvol 1, M R Capecchi 1, K E Bernstein 1
PMCID: PMC508076  PMID: 9153279

Abstract

Angiotensin-converting enzyme (ACE) generates the vasoconstrictor angiotensin II, which plays a critical role in maintenance of blood pressure in mammals. Although significant ACE activity is found in plasma, the majority of the enzyme is bound to tissues such as the vascular endothelium. We used targeted homologous recombination to create mice expressing a form of ACE that lacks the COOH-terminal half of the molecule. This modified ACE protein is catalytically active but entirely secreted from cells. Mice that express only this modified ACE have significant plasma ACE activity but no tissue-bound enzyme. These animals have low blood pressure, renal vascular thickening, and a urine concentrating defect. The phenotype is very similar to that of completely ACE-deficient mice previously reported, except that the renal pathology is less severe. These studies strongly support the concept that the tissue-bound ACE is essential to the control of blood pressure and the structure and function of the kidney.

Full Text

The Full Text of this article is available as a PDF (514.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Azizi M., Rousseau A., Ezan E., Guyene T. T., Michelet S., Grognet J. M., Lenfant M., Corvol P., Ménard J. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest. 1996 Feb 1;97(3):839–844. doi: 10.1172/JCI118484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beldent V., Michaud A., Wei L., Chauvet M. T., Corvol P. Proteolytic release of human angiotensin-converting enzyme. Localization of the cleavage site. J Biol Chem. 1993 Dec 15;268(35):26428–26434. [PubMed] [Google Scholar]
  3. Bernstein K. E., Berk B. C. The biology of angiotensin II receptors. Am J Kidney Dis. 1993 Nov;22(5):745–754. doi: 10.1016/s0272-6386(12)80441-0. [DOI] [PubMed] [Google Scholar]
  4. Bernstein K. E., Martin B. M., Edwards A. S., Bernstein E. A. Mouse angiotensin-converting enzyme is a protein composed of two homologous domains. J Biol Chem. 1989 Jul 15;264(20):11945–11951. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Corvol P., Williams T. A., Soubrier F. Peptidyl dipeptidase A: angiotensin I-converting enzyme. Methods Enzymol. 1995;248:283–305. doi: 10.1016/0076-6879(95)48020-x. [DOI] [PubMed] [Google Scholar]
  7. Cushman D. W., Cheung H. S. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol. 1971 Jul;20(7):1637–1648. doi: 10.1016/0006-2952(71)90292-9. [DOI] [PubMed] [Google Scholar]
  8. Ehlers M. R., Riordan J. F. Angiotensin-converting enzyme: zinc- and inhibitor-binding stoichiometries of the somatic and testis isozymes. Biochemistry. 1991 Jul 23;30(29):7118–7126. doi: 10.1021/bi00243a012. [DOI] [PubMed] [Google Scholar]
  9. Esther C. R., Jr, Howard T. E., Marino E. M., Goddard J. M., Capecchi M. R., Bernstein K. E. Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest. 1996 May;74(5):953–965. [PubMed] [Google Scholar]
  10. Faubert P. F., Chou S. Y., Porush J. G. Regulation of papillary plasma flow by angiotensin II. Kidney Int. 1987 Oct;32(4):472–478. doi: 10.1038/ki.1987.234. [DOI] [PubMed] [Google Scholar]
  11. Friberg P., Sundelin B., Bohman S. O., Bobik A., Nilsson H., Wickman A., Gustafsson H., Petersen J., Adams M. A. Renin-angiotensin system in neonatal rats: induction of a renal abnormality in response to ACE inhibition or angiotensin II antagonism. Kidney Int. 1994 Feb;45(2):485–492. doi: 10.1038/ki.1994.63. [DOI] [PubMed] [Google Scholar]
  12. Hansell P., Sjöquist M., Ulfendahl H. R. Effect of a converting-enzyme inhibitor on vasa recta blood flow in rat kidney. Am J Physiol. 1988 Apr;254(4 Pt 2):F492–F499. doi: 10.1152/ajprenal.1988.254.4.F492. [DOI] [PubMed] [Google Scholar]
  13. Henderson I. W., Oliver J. A., Milne C. M., Balment R. J. Incidence and some functional characteristics of hydronephrosis in Brattleboro rats. Ann N Y Acad Sci. 1982;394:21–29. doi: 10.1111/j.1749-6632.1982.tb37407.x. [DOI] [PubMed] [Google Scholar]
  14. Howard T. E., Shai S. Y., Langford K. G., Martin B. M., Bernstein K. E. Transcription of testicular angiotensin-converting enzyme (ACE) is initiated within the 12th intron of the somatic ACE gene. Mol Cell Biol. 1990 Aug;10(8):4294–4302. doi: 10.1128/mcb.10.8.4294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ito M., Oliverio M. I., Mannon P. J., Best C. F., Maeda N., Smithies O., Coffman T. M. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3521–3525. doi: 10.1073/pnas.92.8.3521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jaspard E., Wei L., Alhenc-Gelas F. Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. J Biol Chem. 1993 May 5;268(13):9496–9503. [PubMed] [Google Scholar]
  17. Kim H. S., Krege J. H., Kluckman K. D., Hagaman J. R., Hodgin J. B., Best C. F., Jennette J. C., Coffman T. M., Maeda N., Smithies O. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2735–2739. doi: 10.1073/pnas.92.7.2735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Krege J. H., Hodgin J. B., Hagaman J. R., Smithies O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension. 1995 May;25(5):1111–1115. doi: 10.1161/01.hyp.25.5.1111. [DOI] [PubMed] [Google Scholar]
  19. Krege J. H., John S. W., Langenbach L. L., Hodgin J. B., Hagaman J. R., Bachman E. S., Jennette J. C., O'Brien D. A., Smithies O. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature. 1995 May 11;375(6527):146–148. doi: 10.1038/375146a0. [DOI] [PubMed] [Google Scholar]
  20. Langford K. G., Shai S. Y., Howard T. E., Kovac M. J., Overbeek P. A., Bernstein K. E. Transgenic mice demonstrate a testis-specific promoter for angiotensin-converting enzyme. J Biol Chem. 1991 Aug 25;266(24):15559–15562. [PubMed] [Google Scholar]
  21. Langford K. G., Zhou Y., Russell L. D., Wilcox J. N., Bernstein K. E. Regulated expression of testis angiotensin-converting enzyme during spermatogenesis in mice. Biol Reprod. 1993 Jun;48(6):1210–1218. doi: 10.1095/biolreprod48.6.1210. [DOI] [PubMed] [Google Scholar]
  22. Mansour S. L., Thomas K. R., Capecchi M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  23. Ng K. K., Vane J. R. Conversion of angiotensin I to angiotensin II. Nature. 1967 Nov 25;216(5117):762–766. doi: 10.1038/216762a0. [DOI] [PubMed] [Google Scholar]
  24. Niimura F., Labosky P. A., Kakuchi J., Okubo S., Yoshida H., Oikawa T., Ichiki T., Naftilan A. J., Fogo A., Inagami T. Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest. 1995 Dec;96(6):2947–2954. doi: 10.1172/JCI118366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rieger K. J., Saez-Servent N., Papet M. P., Wdzieczak-Bakala J., Morgat J. L., Thierry J., Voelter W., Lenfant M. Involvement of human plasma angiotensin I-converting enzyme in the degradation of the haemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline. Biochem J. 1993 Dec 1;296(Pt 2):373–378. doi: 10.1042/bj2960373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Soubrier F., Alhenc-Gelas F., Hubert C., Allegrini J., John M., Tregear G., Corvol P. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9386–9390. doi: 10.1073/pnas.85.24.9386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Waeber B., Nussberger J., Juillerat L., Brunner H. R. Angiotensin converting enzyme inhibition: discrepancy between antihypertensive effect and suppression of enzyme activity. J Cardiovasc Pharmacol. 1989;14 (Suppl 4):S53–S59. [PubMed] [Google Scholar]
  28. Wei L., Alhenc-Gelas F., Corvol P., Clauser E. The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. J Biol Chem. 1991 May 15;266(14):9002–9008. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES