Abstract
We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin, and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A, which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria, rats given untargeted protease (biotin-conjugated without avidin, or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats, targeted protease was again more effective than untargeted protease at reducing proteinuria, and also decreased the size of electron-dense glomerular deposits, hypercholesterolemia, and creatininemia. Inactivated targeted proteases had no effect on proteinuria, hypercholesterolemia, or azotemia. Finally, active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits, proteinuria, hyperlipidemia, and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis, and that targeted protease is more effective than untargeted protease.
Full text
PDF








Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- A controlled study of short-term prednisone treatment in adults with membranous nephropathy. Collaborative Study of the Adult Idiopathic Nephrotic Syndrome. N Engl J Med. 1979 Dec 13;301(24):1301–1306. doi: 10.1056/NEJM197912133012401. [DOI] [PubMed] [Google Scholar]
- Abboud H. E., Ou S. L., Velosa J. A., Shah S. V., Dousa T. P. Dynamics of renal histamine in normal rat kidney and in nephrosis induced by aminonucleoside of puromycin. J Clin Invest. 1982 Feb;69(2):327–336. doi: 10.1172/JCI110456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bolton W. K., Atuk N. O., Sturgill B. C., Westervelt F. B., Jr Therapy of the idiopathic nephrotic syndrome with alternate day steroids. Am J Med. 1977 Jan;62(1):60–70. doi: 10.1016/0002-9343(77)90350-3. [DOI] [PubMed] [Google Scholar]
- Ehrenreich T., Porush J. G., Churg J., Garfinkel L., Glabman S., Goldstein M. H., Grishman E., Yunis S. L. Treatment of idiopathic membranous nephropathy. N Engl J Med. 1976 Sep 30;295(14):741–746. doi: 10.1056/NEJM197609302951401. [DOI] [PubMed] [Google Scholar]
- Gesualdo L., Ricanati S., Hassan M. O., Emancipator S. N., Lamm M. E. Enzymolysis of glomerular immune deposits in vivo with dextranase/protease ameliorates proteinuria, hematuria, and mesangial proliferation in murine experimental IgA nephropathy. J Clin Invest. 1990 Sep;86(3):715–722. doi: 10.1172/JCI114767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guesdon J. L., Ternynck T., Avrameas S. The use of avidin-biotin interaction in immunoenzymatic techniques. J Histochem Cytochem. 1979 Aug;27(8):1131–1139. doi: 10.1177/27.8.90074. [DOI] [PubMed] [Google Scholar]
- Haakenstad A. O., Striker G. E., Mannik M. Removal of glomerular immune complex deposits by excess antigen in chronic mouse model of immune complex disease. Lab Invest. 1983 Mar;48(3):323–331. [PubMed] [Google Scholar]
- Ikemura H., Inouye M. In vitro processing of pro-subtilisin produced in Escherichia coli. J Biol Chem. 1988 Sep 15;263(26):12959–12963. [PubMed] [Google Scholar]
- Kanwar Y. S., Caulin-Glaser T., Gallo G. R., Lamm M. E. Interaction of immune complexes with glomerular heparan sulfate-proteoglycans. Kidney Int. 1986 Dec;30(6):842–851. doi: 10.1038/ki.1986.264. [DOI] [PubMed] [Google Scholar]
- Kaysen G. A., Myers B. D., Couser W. G., Rabkin R., Felts J. M. Mechanisms and consequences of proteinuria. Lab Invest. 1986 May;54(5):479–498. [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Nakazawa M., Emancipator S. N., Lamm M. E. Proteolytic enzyme treatment reduces glomerular immune deposits and proteinuria in passive Heymann nephritis. J Exp Med. 1986 Dec 1;164(6):1973–1987. doi: 10.1084/jem.164.6.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakazawa M., Emancipator S. N., Lamm M. E. Removal of glomerular immune complexes in passive serum sickness nephritis by treatment in vivo with proteolytic enzymes. Lab Invest. 1986 Nov;55(5):551–556. [PubMed] [Google Scholar]
- Rahman M. A., Emancipator S. N., Dunn M. J. Immune complex effects on glomerular eicosanoid production and renal hemodynamics. Kidney Int. 1987 Jun;31(6):1317–1326. doi: 10.1038/ki.1987.145. [DOI] [PubMed] [Google Scholar]
- Rahman M. A., Liu C. N., Dunn M. J., Emancipator S. N. Complement and leukocyte independent proteinuria and eicosanoid synthesis in rat membranous nephropathy. Lab Invest. 1988 Oct;59(4):477–483. [PubMed] [Google Scholar]
- Salant D. J., Belok S., Stilmant M. M., Darby C., Couser W. G. Determinants of glomerular localization of subepithelial immune deposits: effects of altered antigen to antibody ratio, steroids, vasoactive amine antagonists, and aminonucleoside of puromycin on passive Heymann nephritis in rats. Lab Invest. 1979 Jul;41(1):89–99. [PubMed] [Google Scholar]
- Shapira E., Arnon R. Cleavage of one specific disulfide bond in papain. J Biol Chem. 1969 Feb 10;244(3):1026–1032. [PubMed] [Google Scholar]
- Steffen C., Menzel J. In-vivo-Abbau von Immunkomplexen in der Niere durch oral applizierte Enzyme. Wien Klin Wochenschr. 1987 Aug 7;99(15):525–531. [PubMed] [Google Scholar]
- Sugisaki T., Shiwachi S., Ito S., Yonekura M., Kitazawa K., Yamamoto J., Uchida J., Kawasumi H., Sato K., Shibata T. [High-dose gamma globulin therapy for membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis]. Nihon Jinzo Gakkai Shi. 1983 Jun;25(6):697–708. [PubMed] [Google Scholar]
- Valdes A. J., Senterfit L. B., Pollack A. D., Germuth F. G., Jr The effect of antigen excess on chronic immune complex glomerulonephritis. Johns Hopkins Med J. 1969 Jan;124(1):9–17. [PubMed] [Google Scholar]