Inhibition of nuclear factor-kappaB 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-kappaB). We hypothesized that in vivo inhibition of renal NF-kappaB 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-kappaB [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-kappaB 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-kappaB activation (by 73%; P < 0.05) without any effect on UpV. NF-kappaB 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-kappaB activation, tubulointerstitial injury, or UpV in ADR rats.


CONCLUSIONS
The activation of NF-kappaB may have an important role in mediating cortical interstitial monocyte infiltration and tubular injury in nonimmune proteinuric tubulointerstitial inflammation.
Rangan
G K
GK
Department of Renal Medicine, University of Sydney at Westmead Hospital, Australia.
Wang
Y
Y
Tay
Y C
YC
Harris
D C
DC
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004317:Doxorubicin; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008054:Lipid Peroxides / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology*; D009401:Nephrosis / Q000139:chemically induced / Q000503:physiopathology; D011507:Proteinuria / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
D008054:Lipid Peroxides; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D004317:Doxorubicin; D000111:Acetylcysteine