Role of reactive oxygen species in transforming growth factor-beta1-induced extracellular matrix accumulation in renal tubular epithelial cells.

Tubulointerstitial fibrosis, which is characterized by the progressive accumulation of extracellular matrix (ECM), is the main feature of chronic renal allograft dysfunction. Transforming growth factor-β1 (TGF-β1) is the key inducer of tubulointerstitial fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of ECM degradation, is increasingly recognized to play an important role in renal fibrosis. ECM accumulation is the net result of ECM synthesis and degradation. We previously reported that reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) are required for the TGF-β1-induced epithelial-to-mesenchymal transition in renal proximal tubular epithelial cells. In the present study, we examined the role of the ROS-MAPK pathways in TGF-β1-induced fibronectin and PAI-1 up-regulation in renal tubular epithelial cells. Growth arrested, synchronized normal rat kidney epithelial (NRK-52E) cells were stimulated with TGF-β1 (0.2-20 ng/mL) or H(2)O(2) (1-500 μmol/L) in the presence or absence of inhibitors of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (diphenyleneiodonium [DPI] and apocynin [Apo]) and MAPK (PD98059, an MEK inhibitor, or a p38 MAPK inhibitor) for up to 48 hours. Both TGF-β1 and H(2)O(2) increased fibronectin and PAI-1 secretion in dose-dependent manners. Chemical inhibition of NADPH oxidase, extracellular signal-regulated kinase (ERK), or p38 MAPK all inhibited TGF-β1-induced and H(2)O(2)-induced fibronectin and PAI-1 up-regulation. These results suggested that NADPH oxidase-mediated ROS and subsequent ERK and p38 MAPK activation play important roles in ECM accumulation in the renal tubulointerstitium.

Rhyu DY ，Park J ，Sharma BR ，Ha H ... -  《-》

Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.

Rhyu DY ，Yang Y ，Ha H ，Lee GT ，Song JS ，Uh ST ，Lee HB ... -  《JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY》

Role of NAD(P)H oxidase in transforming growth factor-beta1-induced monocyte chemoattractant protein-1 and interleukin-6 expression in rat renal tubular epithelial cells.

Zhang H ，Jiang Z ，Chang J ，Li X ，Zhu H ，Lan HY ，Zhou SF ，Yu X ... -  《-》

Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney.

Ha H ，Lee HB 《NEPHROLOGY》

Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury.

Noh H ，Oh EY ，Seo JY ，Yu MR ，Kim YO ，Ha H ，Lee HB ... -  《-》