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

Naruya Tomita, Ryuichi Morishita, Hui Y. Lan, Kei Yamamoto, Masahide Hashizume, Mitsue Notake, Kaoru Toyosawa, Buichi Fujitani, Wei Mu, David J. Nikolic-Paterson, Robert C. Atkins, Yasufumi Kaneda, Jitsuo Higaki, Toshio Ogihara

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Abstract

Glomerular expression of cytokines, interleukin-1 (IL-1), and tumor necrosis factor-α (TNF-α), together with leukocytic infiltration, are prominent features in crescentic glomerulonephritis. Because these cytokines are targets for nuclear transcription factor-κB (NF-κB), the use of NF-κB decoy oligodeoxynucleotide (ODN) treatment was evaluated in an experimental disease model. Crescentic glomerulonephritis was induced in primed Wistar rats by injection of sheep antiglomerular basement membrane serum. Thirty minutes after injection, rats were anesthetized and the left kidney was perfused with NF-κB 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 heavy proteinuria, glomerular crescents and interstitial lesions, marked leukocytic infiltration, and upregulated renal expression of cytokines (IL-1 and TNF-α) and adhesion molecules (intercellular adhesion molecule-1). In contrast, NF- κB decoy ODN treatment substantially inhibited the disease with a 50% reduction in proteinuria, a threefold reduction in histologic damage, a 50% reduction in leukocytic infiltration, and a 50 to 80% reduction in the renal expression of cytokines and leukocyte adhesion molecules. In conclusion, this study has demonstrated that NF-κB plays a key role in cytokine-mediated renal injury and that NF-κB decoy ODN treatment has clear therapeutic potential in rapidly progressive glomerulonephritis.

Original languageEnglish
Pages (from-to)1244-1252
Number of pages9
JournalJournal of the American Society of Nephrology
Volume11
Issue number7
Publication statusPublished - 1 Jul 2000
Externally publishedYes

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