Toxicology and Applied Pharmacology

Biography

Biography: Hanan H Hagar

Abstract

Implication of oxidative stress and inflammatory mechanisms in adriamycin nephropathy has been suggested. Reactive oxygen species may activate latent matrix metalloproteinases (MMP) that ultimately may induce glomerulosclerosis and fibrosis. Little is known about the effect of MMP inhibitors on focal segmental glomerulosclerosis. This study examined the role of MMP in adriamycin nephropathy as an animal model of glomerulosclerosis using MMP inhibitors, SB-3CT and doxycycline. Forty (40) male Wistar rats were used and allocated into four groups as follows: Normal control rats (n=10), adriamycin treated rats (n=10) and SB-3CT+adriamycin-treated rats (n=10), doxycycline+adriamycin-treated rats (n=10). Adriamycin nephropathy was induced by a single injection of adriamycin (7.5 mg/kg) intraperitoneally. SB-3CT was given at a dose of (1 mg/kg/day, i.p.) while doxycycline was given at a dose of (30 mg/kg/day, i.p.). Therapy was initiated at once after induction of adriamycin nephropathy and continued for 4 weeks. Adriamycin nephropathy resulted in deterioration in lipid profile (elevated serum triglycerides and cholesterol levels) and in kidney function (elevated serum creatinine, BUN) and reduction in serum albumin and total protein levels while their levels were increased in urine. Lipid profile was also changed. Adriamycin-treated rats showed increased tumor necrosis factor-α (TNF-α); intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-b1 and tissue inhibitor of metalloproteinase-1 and 2 (TIMP-1 and TIMP-2) in the kidney as assessed by ELISA technique. MMP activities (MMP-2 and MMP-9) were also induced using zymography technique and western blot analysis. Histological changes were also noted on kidney using hematoxylin and eosin. Immunohistochemical studies revealed increased staining of collagen IV in the renal cortex. MMP inhibitors, doxycycline and SB-3CT significantly reduced serum BUN, creatinine and renal cytokines. Lipid abnormalities were also corrected back to normal. This was parallel to reduction in collagen IV immunostaining and improvement in histological changes. These results suggested that MMP inhibitors may have promise as anti-inflammatory, anti-proliferative and endothelial cell protective. MMP inhibitors may be potential future candidates to provide more effective therapy to halt the development of glomerulosclerosis.