Investigation of the involvement of oxidative stress in metabolic syndrome and the development of new anti-oxidants

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We investigated the possible involvement of oxidative stress in metabolic syndrome using in vivo and in vitro strategies. We examined the effect of angiotensin II (Ang II) on insulin-induced glucose uptake and its intracellular mechanisms in cultured vascular smooth muscle cells (VSMC). Ang II or oxidative stress inhibited insulin-induced glucose uptake, which was reversed by an ERK inhibitor but not by a JNK inhibitor in VSMC. In the chronic mesangioproliferative glomerulonephritis (GN) rat model using uninephrectomy and anti-Thy-1 antibody injection, activation of BMK1 was observed in the glomeruli at day 28 and 56 of GN. In the cultured rat mesangial cells, Ang II and oxidative stress induced BMK1 activation, suggesting that Ang II and oxidative stress involves in an inflammation-induced metabolic syndrome. We also found that BMK1 was activated by H2O2 in a time- and concentration-dependent manner in cultured rat VSMC. The activation of Src tyrosine kinase was also observed which was parallel with the BMK1 activation. We established an experimental model of BMK1 knock downed VSMC using siRNA transfection technology. Furthermore, our results also showed that cell death was increased when H2O2 was added into the BMK1 siRNA transfected VSMC in which BMK1 expression was inhibited. From these findings, it was suggested that BMK1 may play an essential role in protecting cells from oxidative stress-induced apoptosis, which is mediated by Src-mediated signaling pathway. c-Src and BMK1 may be possible targets for the treatment of metabolic syndrome clinically.