The therapeutic effects of saccharolytic and proteolytic enzymes were investigated in models of IgA nephropathy. Mesangial glomerulonephritis was induced in mice by intravenous injection of preformed soluble immune complexes of dextran sulfate and either IgA (J 558) or IgM (MOPC 104 E) anti-dextran MAb (passive model) or by immunization with DEAE dextran (active model). In the passive model, only 30-40% of dextranase-treated mice given IgA or IgM immune complexes had mesangial Ig or dextran deposits, compared with 100% of saline-treated controls (P less than 0.01). There was no significant difference in mice given only protease. In the active model, dextranase and protease separately each reduced glomerular dextran and C3 deposits, and hematuria (P less than 0.01). Dextranase also reduced the glomerular IgA deposits (20 vs. 100% of saline-treated mice) and the frequency and severity of mesangial matrix expansion (both P less than 0.02), but did not reduce the modest IgG or IgM codeposits. Protease reduced IgG and IgM deposits, proteinuria and mesangial hypercellularity compared with saline (P less than 0.02), but did not diminish IgA, and had no effect on mesangial matrix expansion. The combination of dextranase plus protease attenuated all components of glomerular injury as judged by clinical and pathological parameters, but inactivated dextranase plus inactivated protease had no effect on any parameter. We conclude that enzymatic digestion of antigen and antibody can reduce immune deposits, mesangial proliferation, proteinuria, and hematuria in experimental glomerulonephritis.