Received for publication May 29, 2007.
Revised October 1, 2007.
Accepted for publication October 1, 2007.

Angiotensin II Activates ERK Independently of Receptor Tyrosine Kinases in Renal Smooth Muscle Cells: Implications for Blood Pressure Regulation

Abstract

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 MEK/ERK MAPK 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 as compared to 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 AG1478 and AG1296, respectively, demonstrates that Angiotensin II activates ERK in TASMCs, but not RµVSMCs, through transactivation of EGF and PDGF receptors. Additionally, inhibition of Src with its specific inhibitor PP2 abolishes angiotensin II, but not EGF or PDGF, mediated phosphorylation of ERK in RµVSMCs, yet has no effect in TASMCs. The physiological significance of transactivation was examined in vivo utilizing anesthetized Wistar-Kyoto rats with 15 mg/kg PD98059, a 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.

Key words: angiotensin II, epidermal growth factor, hypertension, platelet derived growth factor, src, transactivation