Novel nuclear factor κB activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction

Purpose: We determined whether the novel nuclear factor kappaB activation inhibitor dehydroxy-methylepoxyquinomicin (DHMEQ), which is derived from epoxyquinomicin C, affects renal inflammatory responses in unilateral ureteral obstruction. Materials and 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 kappaB 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 kappaB, 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 mumol. hydroxyproline per gm. tissue versus 3.4 +/- 0. 1, respectively). Conversely daily administration of DHMEQ (8 mg./kg.) significantly inhibited nuclear factor kappaB 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 mumol. hydroxyproline per gm. tissue) in the obstructed kidney. Conclusions: Specific inhibition of nuclear factor kappaB can prevent inflammatory renal responses, suggesting that targeting nuclear factor kappaB activation may be feasible for preventing inflammatory kidney diseases.