The therapeutic efficacy of novel designed nonsteroidal anti-inflammatory drug, M2000 (ß- D- mannuronic acid) on experimental immune complex glomerulonephritis was evaluated. Bovine serum albumin (BSA) nephritis was induced in rats by a subcutaneous immunization and daily intravenous administration of BSA. M2000 solution (30 mg/kg) was administered intraperitoneally at regular 48-hr intervals for 4 weeks. Onset of treatment was day 56. Urinary protein was measured weekly and serum anti-BSA antibody was assessed by ELISA method at different intervals. Animals were killed on day 84 and blood samples and kidney specimens were obtained. Serum (creatinine, blood urea nitrogen, cholesterol, and triglyceride) and urine (protein, urea, and creatinine) determinants were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. The fibrosarcoma cell line was used for assaying tolerability and matrix metalloproteinase type 2 (MMP-2) activity. MMP-2 activity was assessed using zymography. Our data showed that M2000 therapy could significantly reduce the urinary protein excretion in treated rats versus non-treated controls. Anti-BSA antibody titer was lower in treated rats than in controls at the 12th experimental week. Polymorphonuclear neutrophil leukocytes infiltration and glomerular immune complex deposition were less intense in treated rats than in controls. Cytotoxicity analysis of M2000 showed a much higher tolerability compared with other tested drugs (diclofenac, piroxicam and dexamethasone). The inhibitory effect of M2000 in MMP-2 activity was significantly greater than that of dexsamethasone and of piroxicam at a concentration of 200 μg/ml. Moreover, the toxicological study revealed that M2000 had no influence on serum (BUN, creatinine, triglyceride and cholesterol) determinants, urinary protein excretion and glomerular histology in healthy group receiving drug.

Conclusions: These findings suggest that treatment with M2000 can reduce proteinuria, diminish antibody production, and suppress the progression of disease in a rat model of immune complex glomerulonephritis.