Inhibition of nuclear factor-κB activation reduces cortical tubulointerstitial injury in proteinuric rats

Inhibition of nuclear factor-қkgr;B activation reduces cortical tubulointerstitial injury in proteinuric rats.BackgroundProtein-induced chemokine expression in proximal tubular cells is mediated by the transcription factor nuclear factor-kappa B (NF-қkgr;B). We hypothesized that in vivo inhibition of renal NF-қkgr;B activation would reduce interstitial monocyte infiltration in a rat model of nonimmune proteinuric tubulointerstitial inflammation.MethodsMale Wistar rats received a single intravenous injection of doxorubicin hydrochloride [adriamycin (ADR), 7.5 mg/kg] and were studied 7, 14, 21, and 28 days later. In a second study, inhibitors of NF-қkgr;B [N-acetylcysteine (NAC; 150 mg/kg, b.i.d., i.p.), pyrrolidine dithiocarbamate (PDTC, 50 mg/kg, b.i.d., i.p.)] or vehicle were commenced on day 14 after the onset of proteinuria and were continued until day 30.ResultsRats injected with ADR had increased proteinuria (UpV, day 28, 474 ± 57; control, 18 ± 2 mg/day; P < 0.01) and cortical tubulointerstitial injury [tubule cell atrophy, interstitial volume, and monocyte/macrophage (ED-1) infiltration]. Electrophoretic mobility shift assay of nuclear extracts from whole cortex of ADR rats demonstrated that NF-қkgr;B activation (p50/65, p50/c-Rel) increased from day 7 (4.7 ± 0.2 fold-increase above control; P < 0.01) was maximal at day 28 (6.2 ± 0.7; P < 0.01) and correlated with UpV (r = 0.63; P < 0.05) and interstitial ED-1 infiltration (r = 0.67; P < 0.01). Chronic treatment of ADR rats with PDTC suppressed NF-қkgr;B activation (by 73%; P < 0.05) without any effect on UpV. NF-қkgr;B inhibition with PDTC was accompanied by a reduction in tubule cell atrophy (59%; P < 0.01), interstitial volume (49%; P < 0.05) and ED-1 infiltration (48%; P < 0.01), and cortical lipid peroxidation (41%; P < 0.05) compared with vehicle-treated ADR rats. In contrast NAC had no effect on NF-қkgr;B activation, tubulointerstitial injury, or UpV in ADR rats.ConclusionThe activation of NF-қkgr;B may have an important role in mediating cortical interstitial monocyte infiltration and tubular injury in nonimmune proteinuric tubulointerstitial inflammation