The Novel NF-κB Activation Inhibitor Dehydroxymethyl-Epoxyquinomicin Suppresses Anti-Thy1.1-Induced Glomerulonephritis in Rats

Abstract

<abstitle>Abstract</abstitle>Background: NF-κB participates in the transcriptional regulation of numerous genes, and many studies have confirmed the activation of NF-κB in inflammatory renal diseases. Therefore, NF-κB is a promising target for the treatment of these diseases. We tested the effects of dehydroxymethyl-epoxyquinomicin (DHMEQ), a novel NF-κB 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-κB activation was analyzed by a fluorescent electrophoretic mobility shift assay. Results: On day 7, DHMEQ treatment resulted in marked inhibition of NF-κB, decreased proteinuria (223.2 ± 42.3 vs. 434.8 ± 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-κB and thereby suppressed the inflammatory renal responses in rats with Thy1.1 GN.

NF-κB in Renal Inflammation

“…The increasing awareness of NF-B diversity in terms of regulatory components and actions calls for more detailed preclinical studies to pinpoint the timeframe and optimal target for potential clinical therapy. 79 Decreased proteinuria Diabetic nephropathy 80 Decreased inflammation AKI, sepsis 39 Decreased inflammation AKI; zymosan 81 Decreased inflammation 5/6 renal ablation model 82 Decreased inflammation AngII-infused renal injury 54,83 Decreased inflammation Parthenolide Glomerulonephritis 56 Decreased inflammation, proteinuria AKI; cisplatin 87 Decreased inflammation, proteinuria AngII-induced kidney injury 67 Decreased inflammation gliotoxin Glomerulonephritis 56 Decreased inflammation, proteinuria DHMEQ Glomerulonephritis 88 Decreased inflammation, proteinuria Specific approaches decoy B ODN Glomerulonephritis, crescentic 90 Decreased inflammation Allogenic renal transplant 92 Decreased inflammation AKI, ischemia-reperfusion 89 Decreased inflammation UUO 91 Decreased inflammation p50 siRNA AKI, sepsis 39 Improved renal function, decreased inflammation p50 knockout AKI, endotoxemia 40 Prolonged inflammation, increased mortality IB␣ super-repressor Protein overload proteinuria 93 Decreased inflammation DHMEQ, dehydroxymethyl-epoxyquinomicin; ODN, oligodeoxynucleotides; PDTC, pyrrolidinedithiocarbamate; siRNA, small interfering RNA; UUO, unilateral ureteral obstruction.…”

“…88 Dehydroxymethyl-epoxyquinomicin is an inhibitor of RelA nuclear translocation that does not modify IB. 89 There is more specific evidence linking NF-B with renal disease. Prophylactic decoy DNA oligodeoxynucleotides containing the NF-B target sequence inhibit renal injury, leukocytic infiltration, and inflammatory mediators in ischemia-reperfusion AKI, glomerulonephritis, ureteral obstruction, and allogenic renal transplantation.…”

Regulation of human dendritic cells by a novel specific nuclear factor–κB inhibitor, dehydroxymethylepoxyquinomicin

“…Results are those of one representative experiment among three independent experiments. struction and glomerulonephritis models [30,31]. Because DHMEQ has both immunosuppressive and organ preserving effects, it is anticipated that DHMEQ will be applicable to clinical organ transplantation.…”

A nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates GVHD in allogeneic bone marrow transplantation

“…The injection of DHMEQ suppressed the growth of human malignant tumor cell lines that had been injected into nude mice (Kikuchi et al 2003;Starenki et al 2004;Watanabe et al 2005a,b). This agent also improved arthritis in rodents (Wakamatsu et al 2005) and suppressed anti-Thy1.1-induced glomerulonephritis in rats (Kosaka et al 2008). In organ transplantation experiments, DHMEQ suppressed the rejection of transplanted heart or pancreatic islets, resulting in prolongation of graft survival (Goto et al 2012;Kuraya et al 2013).…”