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      The Herbal Medicine Sairei-to Inhibits Proliferation of Rat Mesangial Cells

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      S. Karger AG

      Extracellular signal-regulated kinase, Mitogenesis, Cell cycle, Raf-1, Cyclic AMP

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          Background: The herbal medicine Sairei-to is efficacious in renal diseases where mesangial proliferation is a key event. We examined whether Sairei-to inhibits proliferation of cultured rat mesangial cells and investigated its mechanism of action. Methods: The effect of Sairei-to on [<sup>3</sup>H]-thymidine incorporation stimulated by serum was assessed. Cell cycle was analyzed by flowcytometry. Extracellular signal-regulated kinase (ERK) activity was determined by immunecomplex kinase assay. Tyrosine phosphorylation of cellular proteins, and phosphorylation of ERK and Raf-1 were analyzed by immunoblot. Cyclic AMP was measured by radioimmunoassay. Results: Incubation of mesangial cells for 18 h with water-soluble but not insoluble fraction of Sairei-to inhibited serum-stimulated [<sup>3</sup>H]-thymidine incorporation. In subsequent experiments, water-soluble fraction, at a dose required for a half-maximal response (2 mg/ml), was used. Sairei-to inhibited S-phase entry stimulated by serum. Serum-induced tyrosine phosphorylation of p44 and p42 ERK was inhibited by Sairei-to, but that of other cellular proteins was not affected. Suppression of serum-stimulated ERK activation by Sairei-to was confirmed by immunecomplex kinase assay. Activation of Raf-1, an upstream activator of ERK, was also attenuated by Sairei-to. Incubation of cells with Sairei-to significantly increased the generation of cAMP. Conclusions: Sairei-to inhibits serum-induced DNA synthesis of rat mesangial cells by suppressing Raf-1/ERK cascade probably via cAMP.

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          Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation.

          A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation of mammalian PC12 cells in tissue culture and the genetics of cell fate determination in Drosophila and Caenorhabditis suggest that the extracellular signal-regulated kinase (ERK-regulated) MAPK pathway may be sufficient for these cellular responses. Experiments with PC12 cells also suggest that the duration of ERK activation is critical for cell signaling decisions.

            Author and article information

            S. Karger AG
            September 2002
            26 September 2002
            : 92
            : 3
            : 652-659
            Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
            64112 Nephron 2002;92:652–659
            © 2002 S. Karger AG, Basel

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            Figures: 6, Tables: 1, References: 22, Pages: 8
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