The novel NF-kappaB activation inhibitor dehydroxymethyl-epoxyquinomicin suppresses anti-Thy1.1-induced glomerulonephritis in rats.
BACKGROUND
NF-kappaB participates in the transcriptional regulation of numerous genes, and many studies have confirmed the activation of NF-kappaB in inflammatory renal diseases. Therefore, NF-kappaB is a promising target for the treatment of these diseases. We tested the effects of dehydroxymethyl-epoxyquinomicin (DHMEQ), a novel NF-kappaB 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-kappaB activation was analyzed by a fluorescent electrophoretic mobility shift assay.


RESULTS
On day 7, DHMEQ treatment resulted in marked inhibition of NF-kappaB, 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.


CONCLUSIONS
DHMEQ inhibited NF-kappaB and thereby suppressed the inflammatory renal responses in rats with Thy1.1 GN.
Kosaka
Takeo
T
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Miyajima
Akira
A
Kikuchi
Eiji
E
Horiguchi
Yutaka
Y
Umezawa
Kazuo
K
Ohigashi
Takashi
T
Nakashima
Jun
J
Asano
Tomohiko
T
Oya
Mototsugu
M
D000818:Animals; D000906:Antibodies; D001549:Benzamides / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000627:therapeutic use*; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D018800:Thy-1 Antigens / Q000276:immunology*
D000906:Antibodies; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D018800:Thy-1 Antigens; C464444:dehydroxymethylepoxyquinomicin