In vivo administration of a nuclear transcription factor-kappa B decoy suppresses experimental crescentic glomerulonephritis

Glomerular expression of cytokines, interleukin-l (IL-1), and tumor necrosi s factor-alpha (TNF-alpha), together with leukocytic infiltration, are prom inent features in crescentic glomerulonephritis. Because these cytokines ar e targets for nuclear transcription factor-kappa B (NF-kappa B), the use of NF-kappa B decoy oligodeoxynucleotide (ODN) treatment was evaluated in an experimental disease model. Crescentic glomerulonephritis was induced in pr imed Wistar rats by injection of sheep anti-glomerular basement membrane se rum. Thirty minutes after injection. rats were anesthetized and the left ki dney was perfused with NF-kappa B decoy ODN or scrambled ODN control mixed with a virus-liposome complex, and then killed 7 d later. Animals given the scrambled control ODN developed severe glomerulonephritis by day 7 with he avy proteinuria, glomerular crescents and interstitial lesions, marked leuk ocytic infiltration, and upregulated renal expression of cytokines (IL-1 an d TNF-alpha) and adhesion molecules (intercellular adhesion molecule-1). In contrast, NF-kappa B decoy ODN treatment substantially inhibited the disea se with a 50% reduction in proteinuria, a threefold reduction in histologic damage, a 50% reduction in leukocytic infiltration, and a 50 to 80% reduct ion in the renal expression of cytokines and leukocyte adhesion molecules. In conclusion, this study has demonstrated that NF-kappa B plays a key role in cytokine-mediated renal injury and that NF-kappa B decoy ODN treatment has clear therapeutic potential in rapidly progressive glomerulonephritis.