Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have utilized specific, irreversible inhibitors of cysteine proteinases to examine the role of renal cathepsin B and cathepsin L in the proteinuria which occurs in an experimental model of human glomerular disease. Administration of trans-epoxysuccinyl-L-leucylamido-(3-methyl)butane (Ep475) a specific, irreversible inhibitor of cysteine proteinases, including cathepsins B and L, significantly reduced proteinuria in rats with experimentally induced, neutrophil-independent, anti-GBM antibody disease (controls: 10 +/- 1 mg/24 h, N = 8; anti-GBM antibody disease: 203 +/- 30 mg/24 h, N = 8; anti-GBM antibody disease + Ep475: 112 +/- 13 mg/24 h, mean +/- SEM, N = 6, P less than 0.05). There was a marked reduction in the activity of both cathepsin B and cathepsin L in renal cortices obtained from Ep475-treated rats compared to either saline-treated controls or rats treated with anti-GBM IgG only. Administration of Z-Phe-Tyr(O-t-butyl)CHN2, a specific, irreversible cysteine proteinase inhibitor with a high degree of selectivity toward cathepsin L, also caused a reduction in anti-GBM antibody-induced proteinuria (90 +/- 18 mg/24 h, N = 6, P less than 0.05). This reduction in proteinuria was accompanied by a marked decrease (-84%) in the specific activity of renal cortical cathepsin L in Z-Phe-Tyr(O-t-butyl)CHN2-treated rats. However, cathepsin B activity was unchanged. There was no significant change in the renal anti-GBM antibody uptake, plasma urea nitrogen, or plasma creatinine values in the Z-Phe-Tyr(O-t-butyl)CHN2-treated rats compared to rats treated with anti-GBM IgG only or saline-treated controls. These data document the ability of cysteine proteinase inhibitors to decrease the proteinuria which occurs in a neutrophil-independent model of human anti-GBM antibody disease and suggest an important role for cathepsin L in the pathophysiology of the proteinuria which occurs in this model.
 ...
PMID:Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis. 189 42

Recent in vitro and in vivo studies suggest that cysteine proteinases may play an important role in degradation of the glomerular basement membrane (GBM) by renal glomeruli. However, little information is available concerning the cysteine proteinases present in glomeruli, the distribution of cysteine proteinases in other areas of the kidney, or the potential role of endogenous glomerular cysteine proteinases in GBM degradation. Using well characterized fluorogenic substrates, we have documented the presence of the cysteine proteinases, cathepsins B, H, and L, in glomeruli (0.45 +/- 0.06, 0.39 +/- 0.05, and 0.66 +/- 0.14 mU/mg protein, mean +/- SEM, N = 8) and other fractions prepared from normal rat kidney. The presence of cysteine proteinases in glomeruli was verified by fluorescence microscopy. For each proteinase, the activity was: proportional to the amount of tissue protein and time of incubation; dependent on the presence of exogenously added dithiothreitol; and completely inhibited by the specific cysteine proteinase inhibitor, E-64. The pH optimum for cathepsin B (substrate: Z-Arg-Arg-HNMec) and L (substrate: Z-Phe-Arg-HNMec in the presence of Z-Phe-Phe-CHN2) was approximately pH 6.0 for both glomeruli and renal cortex; while that for cathepsin H (substrate: Arg-HNMec) was approximately 6.5. Incubation of sonicated glomeruli with 3H-GBM under conditions optimal for cysteine proteinase activity (pH 4.5, 1 mM EDTA, and 1 mM dithiothreitol, 37 degrees C) resulted in significant GBM degradation as measured by the release of non-sedimentable (10,000 x g, 10 min) radioactivity or hydroxyproline.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Glomerular basement membrane degradation by endogenous cysteine proteinases in isolated rat glomeruli. 223 82

This study was designed to evaluate the effects of specific and potent cathepsin inhibitors on osteoclastic resorptive functions in vitro by means of a novel ultrastructural assay system. Mouse bone marrow cell-derived osteoclasts were suspended on dentine slices and cultured for 48 hours in the presence of either E-64 (a generalized cysteine proteinase inhibitor) or Z-Phe-Phe-CHN2 (a selective cathepsin L inhibitor). After the removal of cultured osteoclasts, co-cultured dentine slices were examined using electron microscopy: backscattered (BSEM), scanning (SEM), and atomic force (AFM). In morphometric analyses of BSEM images, there were no significant differences in the areas of demineralized dentine surfaces between control and inhibitor-treated groups, suggesting that cathepsin inhibitors had no effect on dentine demineralization by cultured osteoclasts. However, in SEM and AFM observations, both inhibitors remarkably reduced to the same extent, the formation of deep resorption lacunae on dentine slices that had resulted from degradation of matrix collagen. In addition, Z-Phe-Phe-CHN2 treatment produced deeper, ring-like grooves with little collagen exposure in shallow resorption lacunae. These results strongly suggest that (1) cathepsins released by osteoclasts are involved in the formation of deep resorption lacunae, and (2) cathepsin L plays a key role in bone resorption.
 ...
PMID:An ultrastructural evaluation of the effects of cysteine-proteinase inhibitors on osteoclastic resorptive functions. 764 88