Abstract
We employed a novel immunoradiometric assay to measure plasma levels of active renin and prorenin in physiologic and pharmacologic studies designed to characterize renin biosynthesis and processing in response to both chronic and acute stimuli of renin secretion in normal human subjects. Stimulation of renin secretion with prolonged dietary sodium restriction or amiloride resulted in marked increases in the plasma levels of prorenin, active renin, and plasma renin activity (PRA); suppression of renin secretion with indomethacin resulted in parallel decreases in prorenin, active renin, and PRA. In contrast, acute stimulation with upright activity or administration of an angiotensin-converting enzyme inhibitor, which increased active renin and PRA from 2- to 15-fold, had no effect on prorenin levels. Based on studies in cultured human juxtaglomerular tumor cells, it has been proposed that prorenin is secreted constitutively whereas active renin is stored in and released from secretory granules through a regulated pathway. Our studies are consistent with such a model: the parallel changes in active renin and prorenin with experimental maneuvers of long duration suggest that both the constitutive and regulated pathways are altered under these conditions. The increase in active renin levels in the absence of a change in prorenin that occurs in response to acute stimuli presumably represents the release of preformed active enzyme that is stored in secretory granules.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Acker G. M., Galen F. X., Devaux C., Foote S., Papernik E., Pesty A., Menard J., Corvol P. Human chorionic cells in primary culture: a model for renin biosynthesis. J Clin Endocrinol Metab. 1982 Nov;55(5):902–909. doi: 10.1210/jcem-55-5-902. [DOI] [PubMed] [Google Scholar]
- Atlas S. A., Christofalo P., Hesson T., Sealey J. E., Fritz L. C. Immunological evidence that inactive renin is prorenin. Biochem Biophys Res Commun. 1985 Nov 15;132(3):1038–1045. doi: 10.1016/0006-291x(85)91911-4. [DOI] [PubMed] [Google Scholar]
- Atlas S. A., Sealey J. E., Laragh J. H., Moon C. Plasma renin and "prorenin" in essential hypertension during sodium depletion, beta-blockade, and reduced arterial pressure. Lancet. 1977 Oct 15;2(8042):785–789. doi: 10.1016/s0140-6736(77)90723-1. [DOI] [PubMed] [Google Scholar]
- Bangham D. R., Robertson I., Robertson J. I., Robinson C. J., Tree M. An international collaborative study of renin assay: establishment of the international reference preparation of human renin. Clin Sci Mol Med Suppl. 1975 Jun;2:135a–159s. doi: 10.1042/cs048135s. [DOI] [PubMed] [Google Scholar]
- Blundell T., Sibanda B. L., Pearl L. Three-dimensional structure, specificity and catalytic mechanism of renin. Nature. 1983 Jul 21;304(5923):273–275. doi: 10.1038/304273a0. [DOI] [PubMed] [Google Scholar]
- Bouhnik J., Fehrentz J. A., Galen F. X., Seyer R., Evin G., Castro B., Menard J., Corvol P. Immunologic identification of both plasma and human renal inactive renin as prorenin. J Clin Endocrinol Metab. 1985 Feb;60(2):399–401. doi: 10.1210/jcem-60-2-399. [DOI] [PubMed] [Google Scholar]
- Cooper R. M., Murray G. E., Osmond D. H. Trypsin-induced activation of renin precursor in plasma of normal and anephric man. Circ Res. 1977 May;40(5 Suppl 1):I171–I179. [PubMed] [Google Scholar]
- Culler M. D., Tarlatzis B. C., Lightman A., Fernandez L. A., Decherney A. H., Negro-Vilar A., Naftolin F. Angiotensin II-like immunoreactivity in human ovarian follicular fluid. J Clin Endocrinol Metab. 1986 Mar;62(3):613–615. doi: 10.1210/jcem-62-3-613. [DOI] [PubMed] [Google Scholar]
- Cumin F., Evin G., Fehrentz J. A., Seyer R., Castro B., Menard J., Corvol P. Inhibition of human renin by synthetic peptides derived from its prosegment. J Biol Chem. 1985 Aug 5;260(16):9154–9157. [PubMed] [Google Scholar]
- Damkjaer Nielsen M., Giese J., Hesse B., Rasmussen S., Ibsen H. Inactive renin in renal venous blood: biological, methodological and statistical aspects. Acta Med Scand Suppl. 1983;677:80–84. doi: 10.1111/j.0954-6820.1984.tb08636.x. [DOI] [PubMed] [Google Scholar]
- Day R. P., Luetscher J. A. Biochemical properties of big renin extracted from human plasma. J Clin Endocrinol Metab. 1975 Jun;40(6):1085–1093. doi: 10.1210/jcem-40-6-1085. [DOI] [PubMed] [Google Scholar]
- Derkx F. H., Schalekamp M. P., Schalekamp M. A. Two-step prorenin-renin conversion. Isolation of an intermediary form of activated prorenin. J Biol Chem. 1987 Feb 25;262(6):2472–2477. [PubMed] [Google Scholar]
- Derkx F. H., Tan-Tjiong H. L., Man in 't Veld A. J., Schalekamp M. P., Schalekamp M. A. Activation of inactive plasma renin by plasma and tissue kallikreins. Clin Sci (Lond) 1979 Oct;57(4):351–357. doi: 10.1042/cs0570351. [DOI] [PubMed] [Google Scholar]
- Derkx F. H., Wenting G. J., Man in 't Veld A. J., Verhoeven R. P., Schalekamp M. A. Control of enzymatically inactive renin in man under various pathological conditions: implications for the interpretation of renin measurements in peripheral and renal venous plasma. Clin Sci Mol Med. 1978 May;54(5):529–538. doi: 10.1042/cs0540529. [DOI] [PubMed] [Google Scholar]
- GREENWOOD F. C., HUNTER W. M., GLOVER J. S. THE PREPARATION OF I-131-LABELLED HUMAN GROWTH HORMONE OF HIGH SPECIFIC RADIOACTIVITY. Biochem J. 1963 Oct;89:114–123. doi: 10.1042/bj0890114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Galen F. X., Devaux C., Atlas S., Guyenne T., Menard J., Corvol P., Simon D., Cazaubon C., Richer P., Badouaille G. New monoclonal antibodies directed against human renin. Powerful tools for the investigation of the renin system. J Clin Invest. 1984 Sep;74(3):723–735. doi: 10.1172/JCI111488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Galen F. X., Devaux C., Guyenne T., Menard J., Corvol P. Multiple forms of human renin. Purification and characterization. J Biol Chem. 1979 Jun 10;254(11):4848–4855. [PubMed] [Google Scholar]
- Galen F. X., Devaux C., Houot A. M., Menard J., Corvol P., Corvol M. T., Gubler M. C., Mounier F., Camilleri J. P. Renin biosynthesis by human tumoral juxtaglomerular cells. Evidences for a renin precursor. J Clin Invest. 1984 Apr;73(4):1144–1155. doi: 10.1172/JCI111300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Glorioso N., Atlas S. A., Laragh J. H., Jewelewicz R., Sealey J. E. Prorenin in high concentrations in human ovarian follicular fluid. Science. 1986 Sep 26;233(4771):1422–1424. doi: 10.1126/science.3529392. [DOI] [PubMed] [Google Scholar]
- Goldstone R., Horton R., Carlson E. J., Hsueh W. A. Reciprocal changes in active and inactive renin after converting enzyme inhibition in normal man. J Clin Endocrinol Metab. 1983 Feb;56(2):264–268. doi: 10.1210/jcem-56-2-264. [DOI] [PubMed] [Google Scholar]
- Gorden P., Roth J. Plasma insulin: fluctuations in the "big" insulin component in man after glucose and other stimuli. J Clin Invest. 1969 Dec;48(12):2225–2234. doi: 10.1172/JCI106188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gould A. B., Green D. Kinetics of the human renin and human substrate reaction. Cardiovasc Res. 1971 Jan;5(1):86–89. doi: 10.1093/cvr/5.1.86. [DOI] [PubMed] [Google Scholar]
- Hare G. M., Ioannou P., Dubiski S., Osmond D. H. Regulated systemic activation of rat plasma prorenin. Hypertension. 1987 Jul;10(1):122–126. doi: 10.1161/01.hyp.10.1.122. [DOI] [PubMed] [Google Scholar]
- Hsueh W. A., Luetscher J. A., Carlson E. J., Grislis G. Big renin in plasma of healthy subjects on high sodium intake. Lancet. 1978 Jun 17;1(8077):1281–1284. doi: 10.1016/s0140-6736(78)91267-9. [DOI] [PubMed] [Google Scholar]
- Hsueh W. A. Potential effects of renin activation on the regulation of renin production. Am J Physiol. 1984 Aug;247(2 Pt 2):F205–F212. doi: 10.1152/ajprenal.1984.247.2.F205. [DOI] [PubMed] [Google Scholar]
- Kappelgaard A. M., Giese J., Ibsen H., Nielsen M. D., Rabøl A. Different secretion patterns of active and inactive renin in man. Clin Sci Mol Med Suppl. 1978 Dec;4:143s–146s. doi: 10.1042/cs055143s. [DOI] [PubMed] [Google Scholar]
- Kelly R. B. Pathways of protein secretion in eukaryotes. Science. 1985 Oct 4;230(4721):25–32. doi: 10.1126/science.2994224. [DOI] [PubMed] [Google Scholar]
- Mayes D., Furuyama S., Kem D. C., Nugent C. A. A radioimmunoassay for plasma aldosterone. J Clin Endocrinol Metab. 1970 May;30(5):682–685. doi: 10.1210/jcem-30-5-682. [DOI] [PubMed] [Google Scholar]
- Ménard J., Guyenne T. T., Corvol P., Pau B., Simon D., Roncucci R. Direct immunometric assay of active renin in human plasma. J Hypertens Suppl. 1985 Dec;3(3):S275–S278. [PubMed] [Google Scholar]
- Pinet F., Corvol M. T., Dench F., Bourguignon J., Feunteun J., Menard J., Corvol P. Isolation of renin-producing human cells by transfection with three simian virus 40 mutants. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8503–8507. doi: 10.1073/pnas.82.24.8503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poulsen K., Vuust J., Lund T. Renin precursor from mouse kidney identified by cell-free translation of messenger RNA. Clin Sci (Lond) 1980 Oct;59(4):297–299. doi: 10.1042/cs0590297. [DOI] [PubMed] [Google Scholar]
- Pratt R. E., Ouellette A. J., Dzau V. J. Biosynthesis of renin: multiplicity of active and intermediate forms. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6809–6813. doi: 10.1073/pnas.80.22.6809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rumpf K. W., Schächterle B., Schmidt S., Becker K., Scheler F. Different responses of active and inactive plasma renin to various stimuli. Clin Sci Mol Med Suppl. 1978 Dec;4:155s–157s. doi: 10.1042/cs055155s. [DOI] [PubMed] [Google Scholar]
- Sealey J. E., Atlas S. A., Glorioso N., Manapat H., Laragh J. H. Cyclical secretion of prorenin during the menstrual cycle: synchronization with luteinizing hormone and progesterone. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8705–8709. doi: 10.1073/pnas.82.24.8705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sealey J. E., Atlas S. A., Laragh J. H., Oza N. B., Ryan J. W. Activation of a prorenin-like substance in human plasma by trypsin and by urinary kallikrein. Hypertension. 1979 May-Jun;1(3):179–189. doi: 10.1161/01.hyp.1.3.179. [DOI] [PubMed] [Google Scholar]
- Sealey J. E., Atlas S. A., Laragh J. H. Prorenin in plasma and kidney. Fed Proc. 1983 Jul;42(10):2681–2689. [PubMed] [Google Scholar]
- Sealey J. E., Glorioso N., Itskovitz J., Laragh J. H. Prorenin as a reproductive hormone. New form of the renin system. Am J Med. 1986 Dec;81(6):1041–1046. doi: 10.1016/0002-9343(86)90402-x. [DOI] [PubMed] [Google Scholar]
- Sealey J. E., Overlack A., Laragh J. H., Stumpe K. O., Atlas S. A. Effect of captopril and aprotinin on inactive renin. J Clin Endocrinol Metab. 1981 Sep;53(3):626–630. doi: 10.1210/jcem-53-3-626. [DOI] [PubMed] [Google Scholar]
- Simon D., Galen F. X., Devaux C., Soubrier F., Pau B., Menard J., Corvol P. Monoclonal antibody against human renin. J Clin Endocrinol Metab. 1981 Aug;53(2):453–455. doi: 10.1210/jcem-53-2-453. [DOI] [PubMed] [Google Scholar]
- Skinner S. L. Improved assay methods for renin "concentration" and "activity" in human plasma. Methods using selective denaturation of renin substrate. Circ Res. 1967 Apr;20(4):391–402. doi: 10.1161/01.res.20.4.391. [DOI] [PubMed] [Google Scholar]
- Skinner S. L., Thatcher R. L., Whitworth J. A., Horowitz J. D. Extraction of plasma prorenin by human heart. Lancet. 1986 May 3;1(8488):995–997. doi: 10.1016/s0140-6736(86)91270-5. [DOI] [PubMed] [Google Scholar]
- Stockigt J. R., Collins R. D., Biglieri E. G. Determination of plasma renin concentration by angiotensin I immunoassay. Diagnotic import of precise measurement of subnormal renin in hyperaldosteronism. Circ Res. 1971 May;28(5 Suppl):175–191. doi: 10.1161/01.res.28.5.ii-175. [DOI] [PubMed] [Google Scholar]