Abnormal DNA-binding of transcription factors in minimal change nephrotic syndrome

The activation of transcription factors such as nuclear factor kappaB (NF-k appaB) and activator protein 1 (AP-1) plays an important role in regulating the expression of target genes, including those for cytokines involved in pathogenesis of minimal change nephrotic syndrome (MCNS). The therapeutic e ffects of glucocorticoids depend on the glucocorticoid receptor (GR) acting on gene transcription and interacting with certain transcription factors. To explore the role of transcription factors in the pathogenesis of MCNS an d the therapeutic effects of glucocorticoids, we examined the DNA-binding a bilities of NF-kappaB, AP-1, and GR in peripheral blood mononuclear cells ( PBMC) from 6 children with MCNS and 6 healthy controls by electrophoretic m obility shift assay (EMSA). NF-kappaB and AP-1 DNA-binding abilities were s ignificantly increased both at baseline and after stimulation by phorbol 12 -myristate 13-acetate (TPA) in PBMC from MCNS patients compared with contro ls, but declined to normal levels after treatment with dexamethasone (DEX). GR DNA-binding abilities were significantly reduced at baseline and after treatment with TPA, but were enhanced markedly by DEX. There were strong co rrelations between urinary protein and the baseline DNA binding ability of NF-kappaB or AP-1, or GR. These results suggested that the abnormal activat ion of NF-kappaB and AP-1 and the reduction of GR DNA-binding abilities may be involved in the pathogenesis of MCNS. Inhibition of NF-kappaB and AP-1 and enhancement of GR DNA-binding abilities by DEX may form the molecular b asis of the effects of glucocorticoids in MCNS.