The novel NF-κB activation inhibitor dehydroxymethyl-epoxyquinomicin suppresses anti-thy1.1-induced glomerulonephritis in rats

Background: NF-kappa B participates in the transcriptional regulation of numerous genes, and many studies have confirmed the activation of NF-kappa B in inflammatory renal diseases. Therefore, NF-kappa B is a promising target for the treatment of these diseases. We tested the effects of dehydroxymethyl-epoxyquinomicin (DHMEQ), a novel NF-kappa B activation inhibitor, on anti-thy1.1 antibody-induced glomerulonephritis (Thy1.1 GN). Methods: Thy1.1 GN was induced in Sprague-Dawley rats (6/group) by intravenous injection of anti-thy 1.1 antibody. The effects of DHMEQ (8 mg/kg/day) on the glomerular disease were evaluated using periodic acid-Schiff and Masson trichrome stains, immunohistochemistry for proliferating cell nuclear antigen, fibronectin and CD45 ( leukocyte common antigen) and TUNEL staining. NF-kappa B activation was analyzed by a fluorescent electrophoretic mobility shift assay. Results: On day 7, DHMEQ treatment resulted in marked inhibition of NF-kappa B, decreased proteinuria (223.2 +/- 42.3 vs. 434.8 8 16.5 mg/kg/day, p ! 0.05), preserved creatinine clearance (1.93 +/- 0.38 vs. 1.07 +/- 0.29 l/ day, p ! 0.01), decreased glomerular cell proliferation (15.8 +/- 1.2 vs. 31.2 +/- 0.8 nuclei/glomerular cross-section) and mesangial matrix deposition, and an increase in glomerular and tubular apoptosis without inducing any obvious adverse effects. Conclusion: DHMEQ inhibited NF-kappa B and thereby suppressed the inflammatory renal responses in rats with Thy1.1 GN. Copyright (c) 2008 S. Karger AG, Basel.