TY - JOUR T1 - Angiotensin II Activates Extracellular Signal-Regulated Kinase Independently of Receptor Tyrosine Kinases in Renal Smooth Muscle Cells: Implications for Blood Pressure Regulation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 34 LP - 42 DO - 10.1124/jpet.107.126300 VL - 324 IS - 1 AU - Crisanto S. Escano, Jr. AU - Lindsay B. Keever AU - Alexander A. Gutweiler AU - Bradley T. Andresen Y1 - 2008/01/01 UR - http://jpet.aspetjournals.org/content/324/1/34.abstract N2 - Angiotensin II can cause hypertension through enhanced vasoconstriction of renal vasculature. One proposed mechanism for reduction of angiotensin II-induced hypertension is through inhibition of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascade. MEK/ERK has been shown to phosphorylate the regulatory subunit of myosin light chain at identical positions as myosin light chain kinase. There are multiple mechanisms proposed regarding angiotensin II-mediated ERK activation. We hypothesized that renal microvascular smooth muscle cells (RμVSMCs) signal through a unique pathway compared with thoracic aorta smooth muscle cells (TASMCs), which is involved in blood pressure regulation. Use of epidermal growth factor (EGF) and platelet derived growth factor (PDGF) receptor-specific inhibitors 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) and 6,7-dimethoxy-3-phenylquinoxaline (AG1296), respectively, demonstrates that angiotensin II activates ERK in TASMCs, but not RμVSMCs, through transactivation of EGF and PDGF receptors. In addition, inhibition of Src with its specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2) abolishes angiotensin II-, but not EGF-or PDGF-, mediated phosphorylation of ERK in RμVSMCs, yet it has no effect in TASMCs. The physiological significance of transactivation was examined in vivo using anesthetized Wistar-Kyoto rats with 15 mg/kg 2′-amino-3′-methoxyflavone (PD98059), an MEK inhibitor, as well as 20 mg/kg AG1478 and 1.5 mg/kg AG1296 in an acute model of angiotensin II-mediated increase in blood pressure. None of the inhibitors had an effect on basal blood pressure, and only PD98059 reduced angiotensin II-mediated increase in blood pressure. Moreover, in RμVSMCs, but not TASMCs, angiotensin II localizes phosphorylated ERK to actin filaments. In conclusion, angiotensin II signals through a unique mechanism in the renal vascular bed that may contribute to hypertension. The American Society for Pharmacology and Experimental Therapeutics ER -