The cysteine proteinase inhibitor, E-64, reduces proteinuria in an experimental model of glomerulonephritis

Biochem Biophys Res Commun. 1988 Sep 30;155(3):1318-23. doi: 10.1016/s0006-291x(88)81285-3.

Abstract

Proteinuria is a major manifestation of glomerular disease (glomerulonephritis, GN). We examined the effect of trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64), a specific and irreversible cysteine proteinase inhibitor, on urinary protein excretion in a complement- and neutrophil-independent model of antiglomerular basement membrane (GBM) antibody disease. A single injection of rabbit antirat-GBM IgG produced a marked increase in urinary protein excretion 24hr after injection. In two separate studies using different pools of antiGBM IgG, administration of E-64 (5mg every 6h starting 2hr prior to induction of GN) reduced proteinuria (-45 +/- 7%, and -41 +/- 14%, Mean +/- SEM, n = 6; P less than 0.001) in the 24 hour period following induction of the disease. This reduction in urinary protein excretion was accompanied by a marked decrease in the specific activity of the cysteine proteinases cathepsins B and L in glomeruli (B: -97%; L: -84%) and renal cortex (B: -87%; L: -75%) isolated from the same E-64-treated rats compared to same saline-treated controls. These data, combined with the specificity of E-64 for cysteine proteinases, suggest a potential role for cysteine proteinases in the increased GBM permeability and proteinuria in this experimental model of glomerular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin B / analysis
  • Cathepsin L
  • Cathepsins / analysis
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors*
  • Disease Models, Animal
  • Endopeptidases*
  • Glomerulonephritis / chemically induced
  • Glomerulonephritis / enzymology*
  • Kidney Cortex / drug effects
  • Kidney Cortex / enzymology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / enzymology
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Protease Inhibitors / pharmacology*
  • Proteinuria / chemically induced
  • Proteinuria / enzymology
  • Proteinuria / prevention & control*
  • Rabbits
  • Rats

Substances

  • Cysteine Proteinase Inhibitors
  • Protease Inhibitors
  • Cathepsins
  • Endopeptidases
  • Cysteine Endopeptidases
  • Cathepsin B
  • Cathepsin L
  • Ctsl protein, rat
  • Leucine
  • E 64