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

Background. Protein-induced chemokine expression in proximal tubular cells is mediated by the transcription factor nuclear factor-kappa B (NF-kappa B). We hypothesized that in vivo inhibition of renal NF-kappa B activation would reduce interstitial monocyte infiltration in a rat model of nonimmune proteinuric tubulointerstitial inflammation. Methods. Male 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-kappa 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. Results. Rats 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-kappa 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 25 (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-kappa B activation (by 73%; P < 0.05) without any effect on UpV. NF-kappa 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 (45%; 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-kappa B activation, tubulointerstitial injury, or UpV in ADR rats. Conclusion. The activation of NF-kappa B may have an important role in mediating cortical interstitial monocyte infiltration and tubular injury in nonimmune proteinuric tubulointerstitial inflammation.