Nuclear factor-κB inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis

Nuclear factor (NF)-kappaB regulates several genes implicated in the inflammatory response and represents an interesting therapeutic target. We examined the effects of gliotoxin (a fungal metabolite) and parthenolide (a plant extract), which possess anti-inflammatory activities in vitro, on the progression of experimental glomerulonephritis. in the anti-Thy 1.1 rat model, gliotoxin (75 mug/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 mug/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappaB activity, localized in glomerular and tubular cells, was attenuated by either gliotoxin or parthenolide, in association with diminished renal expression of monocyte chemoattractant protein-1 and inducible nitric oxide synthase. in cultured mesangial cells and monocytes, gliotoxin and parthenolide inhibited NF-kappaB activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines; by blocking the phosphorylation/degradation of the IkappaBalpha subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappaB activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.