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NDT Advance Access first published online on October 7, 2009
This version published online on November 4, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp520
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Keisuke Ishizawa1, Yuki Izawa-Ishizawa1, Narantungalag Dorjsuren1, Erika Miki1, Yoshitaka Kihira1, Yasumasa Ikeda1, Shuichi Hamano2, Kazuyoshi Kawazoe3, Kazuo Minakuchi3, Shuhei Tomita1, Koichiro Tsuchiya4 and Toshiaki Tamaki1

1 Department of Pharmacology, The Institute of Health Bioscience, The University of Tokushima Graduate School 2 Department of Pathological Science and Technology, The Institute of Health Bioscience, The University of Tokushima Graduate School 3 Department of Clinical Pharmacy, The Institute of Health Bioscience, The University of Tokushima Graduate School 4 Department of Medical Pharmacology, The Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan

Correspondence and offprint requests to: Keisuke Ishizawa; E-mail: ikeisuke{at}basic.med.tokushima-u.ac.jp



  Abstract

Background. Clinical studies have shown that angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) are able to provide renoprotection independent of their blood pressure lowering effects. ARBs also are reported to suppress oxidative stress, inflammation and certain other cellular responses in a receptor-independent manner. We investigated the effects of an ARB, olmesartan, on the cell migration induced by platelet-derived growth factor (PDGF), a major mitogen involved in the pathogenesis of glomerulonephritis in rat mesangial cells (RMCs).

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 O2·– 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.

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

Received for publication: 9. 2.09
Accepted in revised form: 7. 9.09


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