Possible involvement of nuclear factor-kappaB inhibition in the renal protective effect of oral adsorbent AST-120 in a rat model of chronic renal failure.

Oral adsorbent, AST-120 removes uremic toxins (such as indoxyl sulfate) and retards the progression of chronic renal failure (CRF). However, its mechanism of action has not been precisely clarified. Since indoxyl sulfate elicits renal tubular nuclear factor-kappaB (NF-kappaB) activation in vitro, the present experiments were conducted to elucidate the involvement of NF-kappaB in the beneficial effects of AST-120 using rats with 3/4 nephrectomy, a model of early-stage CRF. Daily administration of AST-120 was started at 6 weeks after 3/4 nephrectomy and continued for 18 weeks. Sham-operated rats, untreated CRF rats and AST-120-treated CRF rats were compared for NF-kappaB DNA-binding activity, gene expression and renal histology. Systolic blood pressure was increased in CRF rats, and this increase was not affected by AST-120. Blood urea nitrogen, serum creatinine and urinary protein were increased in CRF rats. Although AST-120 attenuated these increases, it did not do so to a statistically significant extent. Indoxyl sulfate, which was accumulated in serum of CRF rats, was significantly eliminated by AST-120. Renal cortical NF-kappaB DNA-binding activity was increased in CRF rats. AST-120 significantly inhibited this increase. Monocyte/macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) mRNA observed in CRF rats were attenuated by AST-120. Furthermore, AST-120 significantly blocked renal fibrosis with concomitant inhibition of transforming growth factor beta1 (TGF-beta1) gene expression. It appeared that AST-120 reduced NF-kappaB activation and possibly the activity of NF-kappaB-dependent pathways of interstitial inflammation including MCP-1 expression and macrophage infiltration. The anti-inflammatory effect of AST-120 mediated via inhibition of NF-kappaB is a possible mechanism by which AST-120 retards the progression of renal fibrosis in CRF.