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  • Title: Bcl-xL overexpression protects from apoptosis induced by HMG-CoA reductase inhibitors in murine tubular cells.
    Author: Blanco-Colio LM, Justo P, Daehn I, Lorz C, Ortiz A, Egido J.
    Journal: Kidney Int; 2003 Jul; 64(1):181-91. PubMed ID: 12787408.
    Abstract:
    BACKGROUND: Hyperplasia is attributed to enhanced tubular cell proliferation with unbalanced cell death. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors induce apoptosis in a variety of cell lines, including proximal tubular cells. However, the mechanisms by which statins induce apoptosis in tubular cells have not been fully addressed. METHODS: Apoptosis induced by simvastatin was measured in murine tubular cells with and without overexpressing Bcl-xL. Expression of genes implicated in cell death was studied by Northern and Western blot. RESULTS: The treatment of proliferating murine tubular cells (MCT) with simvastatin induced apoptosis in a time- and dose-dependent manner (0.1 to 1 micromol/L). Apoptosis was correlated with Bcl-xL mRNA and protein down-regulation. By contrast, the treatment with simvastatin did not modify the expression of the proapoptotic protein Bax. Simvastatin treatment was associated with cytochrome C release from the mitochondria to the cytosol. We also observed the presence of active caspase 9 and 3 during apoptosis induced by simvastatin. These effects were reversed by mevalonate, farnesylpyrophosphate (FPP), and geranylgeranylpyrophosphate (GGPP), suggesting the involvement of protein prenylation. Simvastatin appears to alter the balance between cell-life and death-promoting genes, as reflected by the decreased Bcl-xL/Bax ratio. Supporting this hypothesis, overexpression of Bcl-xL reduced the amount of apoptosis induced by simvastatin by 80% when compared with control vector-expressing cells. The overexpression of Bcl-xL also prevented the activation of caspase 9 and 3. CONCLUSION: Our results indicate that down-regulation of Bcl-xL expression mediates apoptosis induced by statins in tubular cells. These results may be relevant to the treatment of disorders characterized by altered tubular proliferation.
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