Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Nov;94(5):2117–2124. doi: 10.1172/JCI117566

Protein C inhibitor is expressed in tubular cells of human kidney.

K P Radtke 1, J A Fernández 1, J S Greengard 1, W W Tang 1, C B Wilson 1, D J Loskutoff 1, I Scharrer 1, J H Griffin 1
PMCID: PMC294656  PMID: 7525654

Abstract

Protein C inhibitor (PCI) is a serpin that inhibits a number of proteases. PCI is found in urine and binds to kidney epithelial cells. To determine if kidney is a source of PCI, cDNA was produced from human kidney total RNA. Sequencing and restriction mapping showed identity between kidney and liver PCI cDNA sequences. Similar cDNAs were obtained from rhesus monkey kidney and liver RNAs. Conditioned medium from the rhesus monkey kidney cell line CCL7.1 was analyzed on immunoblots, showing a 57,000-D protein band that comigrated with human plasma PCI. Immunohistochemical staining and in situ hybridization of human kidney tissue sections showed that kidney PCI antigen and RNA were confined to tubular cells. The findings are consistent with the idea that PCI is synthesized and localized in kidney tissue where it may provide protease inhibitory activity and suggest that complexes of PCI with urokinase found in human urine may be produced locally in the kidney.

Full text

PDF
2124

Images in this article

Selected References

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

  1. Carlier M. F. Actin: protein structure and filament dynamics. J Biol Chem. 1991 Jan 5;266(1):1–4. [PubMed] [Google Scholar]
  2. Desjardins M., Bendayan M. Heterogenous distribution of type IV collagen, entactin, heparan sulfate proteoglycan, and laminin among renal basement membranes as demonstrated by quantitative immunocytochemistry. J Histochem Cytochem. 1989 Jun;37(6):885–897. doi: 10.1177/37.6.2723404. [DOI] [PubMed] [Google Scholar]
  3. Duffy M. J. Plasminogen activators and cancer. Blood Coagul Fibrinolysis. 1990 Dec;1(6):681–687. [PubMed] [Google Scholar]
  4. Ecke S., Geiger M., Resch I., Jerabek I., Sting L., Maier M., Binder B. R. Inhibition of tissue kallikrein by protein C inhibitor. Evidence for identity of protein C inhibitor with the kallikrein binding protein. J Biol Chem. 1992 Apr 5;267(10):7048–7052. [PubMed] [Google Scholar]
  5. Edgington T. S., Glassock R. J., Dixon F. J. Autologous immune complex nephritis induced with renal tubular antigen. I. Identification and isolation of the pathogenetic antigen. J Exp Med. 1968 Mar 1;127(3):555–572. doi: 10.1084/jem.127.3.555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. España F., Berrettini M., Griffin J. H. Purification and characterization of plasma protein C inhibitor. Thromb Res. 1989 Aug 1;55(3):369–384. doi: 10.1016/0049-3848(89)90069-8. [DOI] [PubMed] [Google Scholar]
  7. España F., Gilabert J., Estellés A., Romeu A., Aznar J., Cabo A. Functionally active protein C inhibitor/plasminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma and complexes with prostate-specific antigen. Thromb Res. 1991 Nov 1;64(3):309–320. doi: 10.1016/0049-3848(91)90002-e. [DOI] [PubMed] [Google Scholar]
  8. España F., Vicente V., Tabernero D., Scharrer I., Griffin J. H. Determination of plasma protein C inhibitor and of two activated protein C-inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease. Thromb Res. 1990 Aug 1;59(3):593–608. doi: 10.1016/0049-3848(90)90418-c. [DOI] [PubMed] [Google Scholar]
  9. Faioni E. M., Franchi F., Krachmalnicoff A., Valsecchi C., Viganò G. L., Remuzzi G., Mannucci P. M. Low levels of the anticoagulant activity of protein C in patients with chronic renal insufficiency: an inhibitor of protein C is present in uremic plasma. Thromb Haemost. 1991 Oct 1;66(4):420–425. [PubMed] [Google Scholar]
  10. Geiger M., Heeb M. J., Binder B. R., Griffin J. H. Competition of activated protein C and urokinase for a heparin-dependent inhibitor. FASEB J. 1988 Apr;2(7):2263–2267. doi: 10.1096/fasebj.2.7.3350241. [DOI] [PubMed] [Google Scholar]
  11. Geiger M., Huber K., Wojta J., Stingl L., Espana F., Griffin J. H., Binder B. R. Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo. Blood. 1989 Aug 1;74(2):722–728. [PubMed] [Google Scholar]
  12. Geiger M., Priglinger U., Griffin J. H., Binder B. R. Urinary protein C inhibitor. Glycosaminoclycans synthesized by the epithelial kidney cell line TCL-598 enhance its interaction with urokinase. J Biol Chem. 1991 Jun 25;266(18):11851–11857. [PubMed] [Google Scholar]
  13. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  14. Hawkins D., Cochrane C. G. Glomerular basement membrane damage in immunological glomerulonephritis. Immunology. 1968 May;14(5):665–681. [PMC free article] [PubMed] [Google Scholar]
  15. Heeb M. J., España F., Geiger M., Collen D., Stump D. C., Griffin J. H. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3. J Biol Chem. 1987 Nov 25;262(33):15813–15816. [PubMed] [Google Scholar]
  16. Heeb M. J., Schwarz H. P., White T., Lämmle B., Berrettini M., Griffin J. H. Immunoblotting studies of the molecular forms of protein C in plasma. Thromb Res. 1988 Oct 1;52(1):33–43. doi: 10.1016/0049-3848(88)90038-2. [DOI] [PubMed] [Google Scholar]
  17. Iwamoto T., Nakashima Y., Sueishi K. Secretion of plasminogen activator and its inhibitor by glomerular epithelial cells. Kidney Int. 1990 Jun;37(6):1466–1476. doi: 10.1038/ki.1990.137. [DOI] [PubMed] [Google Scholar]
  18. Keeton M., Eguchi Y., Sawdey M., Ahn C., Loskutoff D. J. Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue. Am J Pathol. 1993 Jan;142(1):59–70. [PMC free article] [PubMed] [Google Scholar]
  19. Kirchheimer J. C., Wojta J., Christ G., Hienert G., Binder B. R. Mitogenic effect of urokinase on malignant and unaffected adjacent human renal cells. Carcinogenesis. 1988 Nov;9(11):2121–2123. doi: 10.1093/carcin/9.11.2121. [DOI] [PubMed] [Google Scholar]
  20. Larsson L. I., Skriver L., Nielsen L. S., Grøndahl-Hansen J., Kristensen P., Danø K. Distribution of urokinase-type plasminogen activator immunoreactivity in the mouse. J Cell Biol. 1984 Mar;98(3):894–903. doi: 10.1083/jcb.98.3.894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Laurell M., Carlson T. H., Stenflo J. Monoclonal antibodies against the heparin-dependent protein C inhibitor suitable for inhibitor purification and assay of inhibitor complexes. Thromb Haemost. 1988 Oct 31;60(2):334–339. [PubMed] [Google Scholar]
  22. Laurell M., Christensson A., Abrahamsson P. A., Stenflo J., Lilja H. Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive system. J Clin Invest. 1992 Apr;89(4):1094–1101. doi: 10.1172/JCI115689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Marlar R. A., Griffin J. H. Deficiency of protein C inhibitor in combined factor V/VIII deficiency disease. J Clin Invest. 1980 Nov;66(5):1186–1189. doi: 10.1172/JCI109952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Matrisian L. M. The matrix-degrading metalloproteinases. Bioessays. 1992 Jul;14(7):455–463. doi: 10.1002/bies.950140705. [DOI] [PubMed] [Google Scholar]
  25. Meijers J. C., Kanters D. H., Vlooswijk R. A., van Erp H. E., Hessing M., Bouma B. N. Inactivation of human plasma kallikrein and factor XIa by protein C inhibitor. Biochemistry. 1988 Jun 14;27(12):4231–4237. doi: 10.1021/bi00412a005. [DOI] [PubMed] [Google Scholar]
  26. Mynderse L. A., Hassell J. R., Kleinman H. K., Martin G. R., Martinez-Hernandez A. Loss of heparan sulfate proteoglycan from glomerular basement membrane of nephrotic rats. Lab Invest. 1983 Mar;48(3):292–302. [PubMed] [Google Scholar]
  27. Pratt C. W., Macik B. G., Church F. C. Protein C inhibitor: purification and proteinase reactivity. Thromb Res. 1989 Mar 15;53(6):595–602. doi: 10.1016/0049-3848(89)90149-7. [DOI] [PubMed] [Google Scholar]
  28. Radtke K. P., Stief T. W., Heimburger N. A new and simple isolation procedure for human protein C inhibitor. Evidence for a second inhibitor for activated protein C present in human plasma. Biol Chem Hoppe Seyler. 1988 Sep;369(9):965–974. doi: 10.1515/bchm3.1988.369.2.965. [DOI] [PubMed] [Google Scholar]
  29. Rondeau E., Ochi S., Lacave R., He C. J., Medcalf R., Delarue F., Sraer J. D. Urokinase synthesis and binding by glomerular epithelial cells in culture. Kidney Int. 1989 Oct;36(4):593–600. doi: 10.1038/ki.1989.235. [DOI] [PubMed] [Google Scholar]
  30. Schmitt M., Jänicke F., Moniwa N., Chucholowski N., Pache L., Graeff H. Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. Biol Chem Hoppe Seyler. 1992 Jul;373(7):611–622. doi: 10.1515/bchm3.1992.373.2.611. [DOI] [PubMed] [Google Scholar]
  31. Stief T. W., Radtke K. P., Heimburger N. Inhibition of urokinase by protein C-inhibitor (PCI). Evidence for identity of PCI and plasminogen activator inhibitor 3. Biol Chem Hoppe Seyler. 1987 Oct;368(10):1427–1433. doi: 10.1515/bchm3.1987.368.2.1427. [DOI] [PubMed] [Google Scholar]
  32. Stump D. C., Thienpont M., Collen D. Purification and characterization of a novel inhibitor of urokinase from human urine. Quantitation and preliminary characterization in plasma. J Biol Chem. 1986 Sep 25;261(27):12759–12766. [PubMed] [Google Scholar]
  33. Suzuki K., Deyashiki Y., Nishioka J., Kurachi K., Akira M., Yamamoto S., Hashimoto S. Characterization of a cDNA for human protein C inhibitor. A new member of the plasma serine protease inhibitor superfamily. J Biol Chem. 1987 Jan 15;262(2):611–616. [PubMed] [Google Scholar]
  34. Suzuki K., Nishioka J., Hashimoto S. Protein C inhibitor. Purification from human plasma and characterization. J Biol Chem. 1983 Jan 10;258(1):163–168. [PubMed] [Google Scholar]
  35. Sørensen P. J., Knudsen F., Nielsen A. H., Dyerberg J. Protein C assays in uremia. Thromb Res. 1989 May 15;54(4):301–310. doi: 10.1016/0049-3848(89)90088-1. [DOI] [PubMed] [Google Scholar]

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

RESOURCES