Submitted on December 5, 2007
Revised on January 16, 2009
Accepted on February 25, 2009
Angiotensin II Receptor Blocker Attenuates the Mechanical Strain Induced Activation of ERK and NADPH Oxidase in Mesangial Cells in the Absence of Angiotensin II
Junichi Yatabe1, Hironobu Sanada1*, Midori Sasaki Yatabe, Shigeatsu Hashimoto, Minoru Yoneda, Robin A. Felder2, Pedro A. Jose3, and Tsuyoshi Watanabe1
1 Fukushima Medical University
2 University of Virgina Medical Center
3 Georgetown University Medical Center
* To whom correspondence should be addressed. E-mail: sanada{at}fmu.ac.jp.
It was recently reported that mechanical strain activates extracellular signal-regulated protein kinases (ERK) without the involvement of angiotensin II (Ang II) in cardiomyocytes. We examined the effects of mechanical strain on ERK phosphorylation levels in the absence of Ang II using rat mesangial cells. The ratio of phosphorylated ERK (p-ERK) to total ERK expression was increased by cyclic mechanical strain in a time- and elongation strength-dependent manner. With olmesartan (Ang II type 1 receptor [AT1R] antagonist) pre-treatment, p-ERK plateau levels decreased in a dose-dependent manner (EC50 = 1.3 x 10-8 M, maximal inhibition 50.6 ± 11.0 % at 10-5 M); a similar effect was observed with RNA interference against AT1aR and Tempol, a superoxide dismutase mimetic. In addition to the inhibition of p-ERK levels, olmesartan blocked the increase in cell-surface and phosphorylated p47phox induced by mechanical strain, and also lowered the mRNA expression levels of NADPH oxidase subunits. These results demonstrate that mechanical strain stimulates AT1R to phosphorylate ERK in mesangial cells in the absence of Ang II. This mechanotransduction mechanism is involved in the oxidative stress caused by NADPH oxidase and is blocked by olmesartan. The inverse agonistic activity of this AT1R blocker may be useful for the prevention of mesangial proliferation and renal damage caused by mechanical strain/oxidative stress regardless of circulating or tissue Ang II levels.
