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From the Institute of Nephrology, School of Medicine, Cardiff University, Cardiff, United Kingdom
Transforming growth factor (TGF)-ß1 is a mediator of the final common pathway of fibrosis associated with progressive renal disease, a process in which proximal tubular cells (PTCs) are known to play an important part. The aim of the current study was to examine the mechanism of PTC TGF-ß1 autoinduction. The addition of TGF-ß1 led to increased amounts of TGF-ß1 mRNA and increased de novo protein synthesis. The addition of TGF-ß1 led to increased phosphorylation of R-Smads and activation of extracellular signal-regulated kinase mitogen-activated protein (MAP) kinase and p38 MAP kinase pathways. Use of a dominant-negative Smad3 (Smad3 DN) expression vector, Smad3 small interfering RNA, and inhibition of extracellular signal-regulated kinase and p38 MAP kinase pathways with the chemical inhibitors PD98059 or SB203580 suggested that activation of these signaling pathways occurred independently. Smad3 DN expression, Smad3 small interfering RNA, or the addition of PD98059 inhibited TGF-ß1-dependent stimulation of TGF-ß1 mRNA. Furthermore, Smad3 blockade specifically inhibited activation of the transcription factor AP-1 by TGF-ß1, whereas PD98059 prevented TGF-ß1-dependent nuclear factor-
B activation. In contrast inhibition of p38 MAP kinase inhibited de novo TGF-ß1 protein synthesis but did not influence TGF-ß1 mRNA expression or activation of either transcription factor. In summary, in PTCs, TGF-ß1 autoinduction requires the coordinated action of independently regulated Smad and non-Smad pathways. Furthermore these pathways regulate distinct transcriptional and translational components of TGF-ß1 synthesis.
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