Cytokine gene expression in adriamycin nephropathy: Effects of antioxidantnuclear factor kappa B inhibitors in established disease

Background/Aim: Inhibition of nuclear factor kappaB with the antioxidant py rrolidine dithiocarbamate (PDTC) reduced tubulointerstitial injury in Adria mycin nephropathy (AN), whereas N-acetylcysteine (NAC) was ineffective. Her e we hypothesize that PDTC reduces the renal cortical expression of nuclear factor KB dependent cytokines in AN. Methods: Male Wistar rats received a single intravenous injection of doxorubicin hydrochloride (7.5 mg/kg). NAC (150 mg/kg twice daily i.p.), PDTC (50 mg/kg twice daily i.p.), or vehicle were commenced on day 14 and continued until day 30. Results: On day 30, mR NAs of selected cytokines were increased in AN (TNF-alpha 3.4-fold, MCP-1 5 .1-fold, IL-10 2.7-fold, TGF-beta1 3.5-fold, all p < 0.05) as determined by RT-PCR. PDTC reduced IL-10 and TGF-<beta>1 mRNAs (p < 0.05), whereas the u pregulation of MCP-1 and TNF-<alpha> mRNAs was not affected. In contrast, N AC increased TNF-alpha and IL-10 mRNAs (p < 0.05). Nuclear protein levels o f activator protein-1 were increased in AN (4.4-fold, p < 0.01) and not sig nificantly altered by PDTC (3.0-fold, p = 0.13) or NAC (5.2-fold, p = 0.18) . Conclusions: The protective effects of PDTC in AN are not associated with a local reduction in TNF-alpha and MCP-1 gene expression. The latter may b e due to continued transactivation by activator protein-1. These data also suggest that IL-10 and TGF-beta1 mRNA expressions are PDTC dependent and ha ve a role in mediating tubulointerstitial injury. Copyright (C) 2000 S. Kar ger AG, Basel.