Novel nuclear factor kappa B activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction.
OBJECTIVE
We determined whether the novel nuclear factor kappa B activation inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which is derived from epoxyquinomicin C, affects renal inflammatory responses in unilateral ureteral obstruction.


METHODS
DHMEQ (8 mg./kg.) was administered to rats 1 day after unilateral ureteral obstruction and every day thereafter. Kidneys were harvested at day 7 after unilateral ureteral obstruction. Tissue nuclear factor kappa B activity and transforming growth factor-beta were determined by electrophoretic mobility shift assay and bioassay using mink lung epithelial cells, respectively. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cellular nuclear antigen and the TUNEL (Intergen, Purchase, New York) assay, respectively. Leukocyte infiltration was detected by immunostaining for CD45. Fibrosis was assessed by measuring tissue hydroxyproline content.


RESULTS
Unilateral ureteral obstruction for 7 days significantly activated nuclear factor kappa B, induced tubular apoptosis, proliferation and interstitial fibrosis in the obstructed kidney of the control group compared with their unobstructed counterparts (30.3 +/- 4.5 nuclei per high power field versus 1.7 +/- 0.4, 25.7 +/- 3.3 nuclei per high power field versus 3.2 +/- 0.4 and 6.2 +/- 0.3 micromol. hydroxyproline per gm. tissue versus 3.4 +/- 0.1, respectively). Conversely daily administration of DHMEQ (8 mg./kg.) significantly inhibited nuclear factor kappa B activation and decreased mean tubular apoptosis (9.5 +/- 2.1 nuclei per high power field), proliferation (10.2 +/- 2.4 nuclei per high power field) and interstitial fibrosis (4.9 +/- 0.4 micromol. hydroxyproline per gm. tissue) in the obstructed kidney.


CONCLUSIONS
Specific inhibition of nuclear factor kappa B can prevent inflammatory renal responses, suggesting that targeting nuclear factor kappa B activation may be feasible for preventing inflammatory kidney diseases.
Miyajima
Akira
A
Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Kosaka
Takeo
T
Seta
Kaori
K
Asano
Tomohiko
T
Umezawa
Kazuo
K
Hayakawa
Masamachi
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D005355:Fibrosis; D020287:In Situ Nick-End Labeling; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007958:Leukocyte Count; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014513:Ureter / Q000276:immunology / Q000473:pathology; D014517:Ureteral Obstruction / Q000276:immunology* / Q000473:pathology
D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; C464444:dehydroxymethylepoxyquinomicin; D017493:Leukocyte Common Antigens