CREB, NF-κB, and NADPH oxidase coordinately upregulate indoxyl sulfate-induced angiotensinogen expression in proximal tubular cells

In chronic kidney disease (CKD), indoxyl sulfate, a uremic toxin, accumulates in serum, and the expression of angiotensinogen (AGT) is upregulated in renal proximaltubular cells. The present study aimed to determine the relationship between indoxyl sulfateand the upregulation of AGT expression in proximaltubular cells. Indoxyl sulfateinduced expression of AGT in rat renal cortexand in cultured human proximaltubular cells (HK-2). In proximaltubular cells, indoxyl sulfateinduced phosphorylation of cAMP response element-binding protein ( CREB) on Ser-133, and small interfering RNA(siRNA) specific to CREBinhibited indoxyl sulfate-induced AGT expression. Our previous study demonstrated that indoxyl sulfateactivated nuclear factor-κB (NF-κB) through reactive oxygen species (ROS) production. NF-κB inhibitors ( pyrrolidine dithiocarbamateand isohelenin), NF-κB p65 siRNA, an antioxidant [N- acetylcysteine(NAC)], and a nicotinamide adenine dinucleotide phosphate( NADPH) oxidaseinhibitor [diphenyleneiodon...