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Nakamura, A,Imaizumi, A,Yanagawa, Y,Niimi, R,Kohsaka, T,Johns, EJ;
2003
March
Biochemical Pharmacology
beta 2-adrenoceptor activation inhibits Shiga toxin2-induced apoptosis of renal tubular epithelial cells
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Optional Fields
MAPK caspase HUS cAMP-PKA renal tubule HEMOLYTIC-UREMIC SYNDROME CYCLIC-AMP ESCHERICHIA-COLI NEUTROPHIL APOPTOSIS SIGNALING PATHWAY INDUCE APOPTOSIS TNF-ALPHA CAMP TOXIN KINASE
66
343
353
Apoptosis is regulated by several pathways, such as caspases, mitogen activated protein kinase (MAPK) and cAMP/cAMP-dependent protein kinase A (PKA) cascade. This study investigated the effect Of beta(2)-adrenoceptor activation on Shiga toxin (Stx)2-induced apoptosis in renal tubular cells and the contribution of these signalling pathways. Cultured human adenocarcinoma-derived tubular cells were exposed to Stx2 (64 pg/mL) for 2-24 hr following the addition of the beta(2)-adrenoceptor agonist (terbutaline) to the incubation medium. Stx2-induced apoptosis and its amelioration by beta(2)-adrenoceptor activation was confirmed using DNA degradation assays and by flow cytometry for annexin V, mitochondrial membrane potential and caspase(-3 and -7) activity. Exposure of cells to Stx2 for 24 hr increased the DNA fragmentation to 11.6 +/- 0.9%, compared to 3.3 +/- 0.2% in control cells (P < 0.05) but was decreased to approximately 5-7% (P < 0.05) in the presence of terbutaline. Furthermore, Stx2-stimulated apoptosis, detected by TUNEL, annexin V and mitochondrial potential, was inhibited by terbutatine (P < 0.05) which was prevented by cAMP-PKA inhibitors and a beta(2)-adrenoceptor antagonist. However, inhibition of Stx2-mediated caspase activity by terbutaline was partially blocked by cAMP-PKA inhibitors. On the other hand, p38MAPK inhibition by terbutaline prevented Stx2-induced apoptosis and caspase activity through a cAMP-independent pathway via beta(2)-adrenoceptor. These data indicate that beta(2)-adrenoceptor activation can inhibit Stx2-induced apoptosis of the cells, which may be caused by a reduction in caspase activity through cAMP-PKA activation and the p38MAPK pathway. (C) 2003 Elsevier Science Inc. All rights reserved.
DOI 10.1016/S0006-2952(03)00256-9
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