Angiotensin II receptor blocker attenuates PDGF-induced mesangial cell migration in a receptor-independent manner

作者：Ishizawa Keisuke^*; Izawa Ishizawa Yuki; Dorjsuren Narantungalag; Miki Erika; Kihira Yoshitaka; Ikeda Yasumasa; Hamano Shuichi; Kawazoe Kazuyoshi; Minakuchi Kazuo; Tomita Shuhei; Tsuchiya Koichiro; Tamaki Toshiaki

来源：Nephrology Dialysis Transplantation, 2010, 25(2): 364-372.

DOI：10.1093/ndt/gfp520

• angiotensin II receptor blocker
• big mitogen-activated protein kinase 1
• mesangial cells
• oxidative stress
• platelet-derived growth factor

Methods. Cell migration was determined by a modified Boyden chamber assay. The intracellular signalling pathway was examined by western blotting. AT1 receptor expression was knocked down by small interfering RNAs. The intracellular reactive oxygen species (ROS) was measured by using a fluorescent probe. The O(2)(center dot-) scavenging activities were studied by the electron paramagnetic resonance-spin trapping method.
Results. PDGF-induced cell migration was inhibited by olmesartan in AT1 receptor knockdown RMCs. Olmesartan attenuated big mitogen-activated protein (MAP) kinase 1 (BMK1) and Src activation by PDGF in AT1 receptor knockdown RMCs. PDGF-induced BMK1 activation was suppressed by the Src family tyrosine kinase inhibitors, indicating that Src exists upstream of BMK1. The NADPH oxidase inhibitors inhibited not only PDGF-induced BMK1 and Src activation but also RMC migration. The elevation in ROS generation induced by PDGF was decreased by olmesartan. Olmesartan displayed neither directly ROS scavenging activity nor the inhibition of ROS-mediated intracellular signalling in RMCs.
Conclusions. Olmesartan attenuates ROS generation by PDGF, leading to the subsequent inhibition of Src/ BMK1/migration in an AT1 receptor-independent manner in RMCs.

• 出版日期2010-2