Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis

Abstract

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 < 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)CHN 2, 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 < 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)CHN 2-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)CHN 2 -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-in-dependent 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.