Angiotensin II receptor blocker attenuates PDGF-induced mesangial cell migration in a receptor-independent manner.
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 O(2)(.-) 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.
Ishizawa
Keisuke
K
Department of Pharmacology, The Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan. ikeisuke@basic.med.tokushima-u.ac.jp
Izawa-Ishizawa
Yuki
Y
Dorjsuren
Narantungalag
N
Miki
Erika
E
Kihira
Yoshitaka
Y
Ikeda
Yasumasa
Y
Hamano
Shuichi
S
Kawazoe
Kazuyoshi
K
Minakuchi
Kazuo
K
Tomita
Shuhei
S
Tsuchiya
Koichiro
K
Tamaki
Toshiaki
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D013777:Tetrazoles; C437965:olmesartan