Minimal-change nephrotic syndrome (MCNS) is a renal disease characterized by heavy glomerular proteinuria and increased production of cytokines by immune cells. Because of the central role of nuclear factor-kappaB (NF-kappaB) in the regulation of cytokine expression, its activity during the relapse and remission phases of steroid-sensitive MCNS was analyzed. During relapse, nuclear extracts from peripheral blood mononuclear cells displayed high levels of NF-kappaB DNA-binding activity, consisting primarily of p50/RelA (p65) complexes. NF-kappaB p65 and IkappaBalpha proteins were barely detected or not detected in cytosolic fractions during relapse, in contrast to remission. The lack of expression of IkappaBalpha protein was associated with downregulation of IkappaBalpha mRNA and increases in the levels of the mRNA encoding the proteasome alpha2 subunit proteolytic pathway. In addition, inhibition of proteasome activity induced cytosolic accumulation of phosphorylated IkappaBalpha and significant reductions in the NF-kappaB binding activity in nuclear extracts from peripheral blood mononuclear cells from patients experiencing relapses. These results suggest that alterations in the NF-kappaB/IkappaBalpha regulatory feedback loop may contribute to the immunologic abnormalities that occur in steroidsensitive MCNS.