title: 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.
abstract: 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 (EC(50) = 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(1A)R) 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.
authors.affiliation: Department of Internal Medicine 3, Fukushima Medical University, School of Medicine, Fukushima, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Yatabe
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sanada
authors.forename: Midori Sasaki
authors.initials: MS
authors.lastname: Yatabe
authors.forename: Shigeatsu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoneda
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D035683:MicroRNAs / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D013777:Tetrazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002614:Chelating Agents; D007093:Imidazoles; D035683:MicroRNAs; D019384:Nucleic Acid Synthesis Inhibitors; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015638:Cytochalasin D; D004533:Egtazic Acid; C437965:olmesartan; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D048049:Extracellular Signal-Regulated MAP Kinases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid