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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/F1052    most recent 00580.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yatabe, J. Articles by Watanabe, T. Search for Related Content PubMed PubMed Citation Articles by Yatabe, J. Articles by Watanabe, T.

Angiotensin II type 1 receptor blocker attenuates the activation of ERK and NADPH oxidase by mechanical strain in mesangial cells in the absence of angiotensin II

¹Department of Internal Medicine 3, Fukushima Medical University School of Medicine, Fukushima, Japan; ²Department of Pathology, University of Virginia Health System, Charlottesville, Virginia; and ³Departments of Pediatrics, Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia

Submitted 5 December 2007 ; accepted in final form 25 February 2009

It has been 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] pretreatment, 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 Ang II type 1A receptor (AT_1AR) and Tempol, a superoxide dismutase mimetic. In addition to the inhibition of p-ERK levels, olmesartan blocked the increase in cell surface and phosphorylated p47^phox 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.

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