The cysteine proteinase inhibitor, E-64, reduces proteinuria in an experimental model of glomerulonephritis.
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.
Baricos
W H
WH
Department of Biochemistry, Tulane Medical School, New Orleans, LA 70112.
O'Connor
S E
SE
Cortez
S L
SL
Wu
L T
LT
Shah
S V
SV
D000818:Animals; D002401:Cathepsin B / Q000032:analysis; D056668:Cathepsin L; D002403:Cathepsins / Q000032:analysis; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D004195:Disease Models, Animal; D010450:Endopeptidases; D005921:Glomerulonephritis / Q000139:chemically induced / Q000201:enzymology*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011507:Proteinuria / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D011817:Rabbits; D051381:Rats
D015853:Cysteine Proteinase Inhibitors; D011480:Protease Inhibitors; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534280:Ctsl protein, rat; D007930:Leucine; C024974:E 64