Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 1;97(11):2478–2484. doi: 10.1172/JCI118694

The kidney is a major site of alpha(2)-antiplasmin production.

P A Menoud 1, N Sappino 1, M Boudal-Khoshbeen 1, J D Vassalli 1, A P Sappino 1
PMCID: PMC507332  PMID: 8647939

Abstract

The serpin alpha2-antiplasmin (alpha2-AP) is the major circulating inhibitor of plasmin; it plays a determining role in the regulation of intravascular fibrinolysis, In addition to blood plasma, plasmin formation occurs in various organs where it is thought to fulfill a spectrum of functions not restricted to clot lysis. Alpha2-AP is synthesized by hepatocytes, but other possible sites of production have not been investigated. To explore the potential extravascular contribution of alpha2-AP in the regulation of proteolysis, we have isolated the murine alpha2-AP cDNA and determined its mRNA distribution in adult tissues. In addition to liver, kidneys are major sites of alpha2-AP mRNA accumulation in the mouse. The transcript is present in epithelial cells lining the convoluted portion of proximal tubules, and its accumulation is under androgen control. Human kidneys also contain high levels of alpha2-AP mRNA. Moderate amounts Of alpha2-AP mRNA are detected in other murine tissues such as muscle, intestine, central nervous system, and placenta. Our observations indicate that alpha2-AP can be synthesized in a number of tissues, where it could function as a distal regulator of plasmin-mediated extracellular proteolysis.

Full Text

The Full Text of this article is available as a PDF (673.0 KB).

Selected References

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

  1. Aoki N. Molecular genetics of alpha 2 plasmin inhibitor. Adv Exp Med Biol. 1990;281:195–200. doi: 10.1007/978-1-4615-3806-6_19. [DOI] [PubMed] [Google Scholar]
  2. Asadi F. K., Dimaculangan D. D., Berger F. G. Androgen regulation of gene expression in primary epithelial cells of the mouse kidney. Endocrinology. 1994 Mar;134(3):1179–1187. doi: 10.1210/endo.134.3.8119157. [DOI] [PubMed] [Google Scholar]
  3. Belin D., Vassalli J. D., Combépine C., Godeau F., Nagamine Y., Reich E., Kocher H. P., Duvoisin R. M. Cloning, nucleotide sequencing and expression of cDNAs encoding mouse urokinase-type plasminogen activator. Eur J Biochem. 1985 Apr 15;148(2):225–232. doi: 10.1111/j.1432-1033.1985.tb08829.x. [DOI] [PubMed] [Google Scholar]
  4. Berger F. G., Watson G. Androgen-regulated gene expression. Annu Rev Physiol. 1989;51:51–65. doi: 10.1146/annurev.ph.51.030189.000411. [DOI] [PubMed] [Google Scholar]
  5. Carmeliet P., Schoonjans L., Kieckens L., Ream B., Degen J., Bronson R., De Vos R., van den Oord J. J., Collen D., Mulligan R. C. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994 Mar 31;368(6470):419–424. doi: 10.1038/368419a0. [DOI] [PubMed] [Google Scholar]
  6. Carrell R. W., Evans D. L., Stein P. E. Mobile reactive centre of serpins and the control of thrombosis. Nature. 1991 Oct 10;353(6344):576–578. doi: 10.1038/353576a0. [DOI] [PubMed] [Google Scholar]
  7. Cartier N., Lacave R., Vallet V., Hagege J., Hellio R., Robine S., Pringault E., Cluzeaud F., Briand P., Kahn A. Establishment of renal proximal tubule cell lines by targeted oncogenesis in transgenic mice using the L-pyruvate kinase-SV40 (T) antigen hybrid gene. J Cell Sci. 1993 Mar;104(Pt 3):695–704. doi: 10.1242/jcs.104.3.695. [DOI] [PubMed] [Google Scholar]
  8. Catterall J. F., Kontula K. K., Watson C. S., Seppänen P. J., Funkenstein B., Melanitou E., Hickok N. J., Bardin C. W., Jänne O. A. Regulation of gene expression by androgens in murine kidney. Recent Prog Horm Res. 1986;42:71–109. doi: 10.1016/b978-0-12-571142-5.50006-9. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Christensen S., Sottrup-Jensen L. Bovine alpha 2-antiplasmin. N-terminal and reactive site sequence. FEBS Lett. 1992 Nov 2;312(1):100–104. doi: 10.1016/0014-5793(92)81419-m. [DOI] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Harrison P., Cramer E. M. Platelet alpha-granules. Blood Rev. 1993 Mar;7(1):52–62. doi: 10.1016/0268-960x(93)90024-x. [DOI] [PubMed] [Google Scholar]
  13. Henderson C. J., Wolf C. R. Evidence that the androgen receptor mediates sexual differentiation of mouse renal cytochrome P450 expression. Biochem J. 1991 Sep 1;278(Pt 2):499–503. doi: 10.1042/bj2780499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holmberg L., Lecander I., Astedt B. Binding of urokinase to plasma proteinase inhibitors. Scand J Clin Lab Invest. 1980;40(8):743–747. doi: 10.3109/00365518009095590. [DOI] [PubMed] [Google Scholar]
  15. Huber R., Carrell R. W. Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins. Biochemistry. 1989 Nov 14;28(23):8951–8966. doi: 10.1021/bi00449a001. [DOI] [PubMed] [Google Scholar]
  16. Jensen P. J., Baird J., Morioka S., Lessin S., Lazarus G. S. Epidermal plasminogen activator is abnormal in cutaneous lesions. J Invest Dermatol. 1988 Jun;90(6):777–782. doi: 10.1111/1523-1747.ep12461494. [DOI] [PubMed] [Google Scholar]
  17. Keohane M. E., Hall S. W., VandenBerg S. R., Gonias S. L. Secretion of alpha 2-macroglobulin, alpha 2-antiplasmin, and plasminogen activator inhibitor-1 by glioblastoma multiforme in primary organ culture. J Neurosurg. 1990 Aug;73(2):234–241. doi: 10.3171/jns.1990.73.2.0234. [DOI] [PubMed] [Google Scholar]
  18. Kimura S., Aoki N. Cross-linking site in fibrinogen for alpha 2-plasmin inhibitor. J Biol Chem. 1986 Nov 25;261(33):15591–15595. [PubMed] [Google Scholar]
  19. Macfarlane D. E., Dahle C. E. Isolating RNA from whole blood--the dawn of RNA-based diagnosis? Nature. 1993 Mar 11;362(6416):186–188. doi: 10.1038/362186a0. [DOI] [PubMed] [Google Scholar]
  20. Meseguer A., Catterall J. F. Mouse kidney androgen-regulated protein messenger ribonucleic acid is expressed in the proximal convoluted tubules. Mol Endocrinol. 1987 Aug;1(8):535–541. doi: 10.1210/mend-1-8-535. [DOI] [PubMed] [Google Scholar]
  21. Moll S., Schifferli J. A., Huarte J., Lemoine R., Vassalli J. D., Sappino A. P. LPS induces major changes in the extracellular proteolytic balance in the murine kidney. Kidney Int. 1994 Feb;45(2):500–508. doi: 10.1038/ki.1994.65. [DOI] [PubMed] [Google Scholar]
  22. Morioka S., Lazarus G. S., Baird J. L., Jensen P. J. Migrating keratinocytes express urokinase-type plasminogen activator. J Invest Dermatol. 1987 Apr;88(4):418–423. doi: 10.1111/1523-1747.ep12469754. [DOI] [PubMed] [Google Scholar]
  23. Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rella C., Coviello M., Quaranta M., Paradiso A. Tissue-type plasminogen activator as marker of functional steroid receptors in human breast cancer. Thromb Res. 1993 Jan 15;69(2):209–220. doi: 10.1016/0049-3848(93)90046-q. [DOI] [PubMed] [Google Scholar]
  25. Rickles R. J., Darrow A. L., Strickland S. Molecular cloning of complementary DNA to mouse tissue plasminogen activator mRNA and its expression during F9 teratocarcinoma cell differentiation. J Biol Chem. 1988 Jan 25;263(3):1563–1569. [PubMed] [Google Scholar]
  26. Sachs A., Wahle E. Poly(A) tail metabolism and function in eucaryotes. J Biol Chem. 1993 Nov 5;268(31):22955–22958. [PubMed] [Google Scholar]
  27. Saito H. Alpha 2-plasmin inhibitor and its deficiency states. J Lab Clin Med. 1988 Dec;112(6):671–678. [PubMed] [Google Scholar]
  28. Samama M., Castel M., Matsuo O., Hoylaerts M., Lijnen H. R. Comparative study of the activity of high and low molecular weight urokinase in the presence of fibrin. Thromb Haemost. 1982 Feb 26;47(1):36–40. [PubMed] [Google Scholar]
  29. Sappino A. P., Huarte J., Belin D., Vassalli J. D. Plasminogen activators in tissue remodeling and invasion: mRNA localization in mouse ovaries and implanting embryos. J Cell Biol. 1989 Nov;109(5):2471–2479. doi: 10.1083/jcb.109.5.2471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sappino A. P., Huarte J., Vassalli J. D., Belin D. Sites of synthesis of urokinase and tissue-type plasminogen activators in the murine kidney. J Clin Invest. 1991 Mar;87(3):962–970. doi: 10.1172/JCI115104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sappino A. P., Madani R., Huarte J., Belin D., Kiss J. Z., Wohlwend A., Vassalli J. D. Extracellular proteolysis in the adult murine brain. J Clin Invest. 1993 Aug;92(2):679–685. doi: 10.1172/JCI116637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sasaki T., Morita T., Iwanaga S. Identification of the plasminogen-binding site of human alpha 2-plasmin inhibitor. J Biochem. 1986 Jun;99(6):1699–1705. doi: 10.1093/oxfordjournals.jbchem.a135645. [DOI] [PubMed] [Google Scholar]
  33. Soreq H., Miskin R. Plasminogen activator in the rodent brain. Brain Res. 1981 Jul 20;216(2):361–374. doi: 10.1016/0006-8993(81)90138-4. [DOI] [PubMed] [Google Scholar]
  34. Störkel S., van den Berg E. Morphological classification of renal cancer. World J Urol. 1995;13(3):153–158. doi: 10.1007/BF00184870. [DOI] [PubMed] [Google Scholar]
  35. Sumi Y., Ichikawa Y., Nakamura Y., Miura O., Aoki N. Expression and characterization of pro alpha 2-plasmin inhibitor. J Biochem. 1989 Oct;106(4):703–707. doi: 10.1093/oxfordjournals.jbchem.a122920. [DOI] [PubMed] [Google Scholar]
  36. Tone M., Kikuno R., Kume-Iwaki A., Hashimoto-Gotoh T. Structure of human alpha 2-plasmin inhibitor deduced from the cDNA sequence. J Biochem. 1987 Nov;102(5):1033–1041. doi: 10.1093/oxfordjournals.jbchem.a122141. [DOI] [PubMed] [Google Scholar]
  37. Vassalli J. D., Huarte J., Bosco D., Sappino A. P., Sappino N., Velardi A., Wohlwend A., Ernø H., Monard D., Belin D. Protease-nexin I as an androgen-dependent secretory product of the murine seminal vesicle. EMBO J. 1993 May;12(5):1871–1878. doi: 10.1002/j.1460-2075.1993.tb05835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Vassalli J. D., Sappino A. P., Belin D. The plasminogen activator/plasmin system. J Clin Invest. 1991 Oct;88(4):1067–1072. doi: 10.1172/JCI115405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 1986 Jun 11;14(11):4683–4690. doi: 10.1093/nar/14.11.4683. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES