Nuclear Factor-κB Inhibitors as Potential Novel Anti-Inflammatory Agents for the Treatment of Immune Glomerulonephritis

Abstract

Nuclear factor (NF)-kappa B 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 micro g/rat/day, 10 days, n = 18 rats) markedly reduced proteinuria, glomerular lesions, and monocyte infiltration. In anti-mesangial cell nephritis in mice, parthenolide (70 micro g/mouse/day, 7 days, n = 17 mice) significantly decreased proteinuria, hematuria, and glomerular proliferation. NF-kappa B 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-kappa B activation and expression of inflammatory genes induced by lipopolysaccharide and cytokines, by blocking the phosphorylation/degradation of the I kappa B(alpha) subunit. In summary, gliotoxin and parthenolide prevent proteinuria and renal lesions by inhibiting NF-kappa B activation and expression of regulated genes. This may represent a novel approach for the treatment of immune and inflammatory renal diseases.

CTGF Promotes Inflammatory Cell Infiltration of the Renal Interstitium by Activating NF-κB

“…26 This NF-B inhibitor has previously shown beneficial effects in several experimental models of renal damage. 22,27 Treatment with parthenolide ameliorated CTGF-induced renal damage and markedly diminished the presence of infiltrating monocytes/macrophages and T cells in renal interstitium ( Figure 1). Parthenolide significantly diminished renal NF-B activation caused by CTGF (Figure 2).…”

“…The dose of parthenolide was established based on previous experience in the lab. 22,27 We perfused the kidneys in situ with cold saline before removal. One kidney from each mouse was fixed in buffered formalin, embed- ded in paraffin, and used for immunohistochemistry.…”

NF-κB in Renal Inflammation

“…7,15,44,[55][56][57] Most studies describe the presence of RelA and p50 in the complexes, although c-rel is also localized to NF-B DNA-binding complexes in some studies. 58 There is less information on noncanonical pathway components.…”

Continuous, noninvasive monitoring of local microscopic inflammation using a genetically engineered cell-based biosensor

“…9,10 During the course of experimental and human glomerulonephritis, activation of NF-kB occurs, [11][12][13] leading to the expression of inflammation-associated genes in glomerular cells. 14,15 The kB enhancer element should be useful as a sensor for glomerulonephritis.…”