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(Hypertension. 2008;51:719.)
© 2008 American Heart Association, Inc.

Original Articles

₂-Adrenoceptors Enhance Angiotensin II–Induced Renal Vasoconstriction

Role for NADPH Oxidase and RhoA

Edwin K. Jackson; Delbert G. Gillespie; Chongxue Zhu; Jin Ren; Lefteris C. Zacharia; Zaichuan Mi

From the Center for Clinical Pharmacology, Departments of Pharmacology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.

Correspondence to Edwin K. Jackson, Center for Clinical Pharmacology, 100 Technology Dr, Suite 450, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219. E-mail edj+@pitt.edu

₂-Adrenoceptors potentiate renal vascular responses to angiotensin II via coincident signaling at phospholipase C. This leads to increased activation of the phospholipase C/protein kinase C/c-src pathway. Studies suggest that c-src activates the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase/superoxide system, and reactive oxygen species stimulate the RhoA/Rho kinase pathway. Therefore, we hypothesized that NADPH oxidase/superoxide and RhoA/Rho kinase are downstream components of the signal transduction pathway that mediate the interaction between ₂-adrenoceptors and angiotensin II on renal vascular resistance. In rat kidneys, both in vivo and in vitro, intrarenal infusions of angiotensin II increased renal vascular resistance, and UK14,304 (₂-adrenoceptor agonist) enhanced this response. Intrarenal Tempol (superoxide dismutase mimetic) or Y27632 (Rho kinase inhibitor) abolished the interaction between UK14,304 and angiotensin II both in vivo and in vitro. The interaction was also blocked by inhibitors of NADPH oxidase (in vivo using chronic gp91ds-tat administration and in vitro with diphenyleneiodonium). In cultured preglomerular vascular smooth muscle cells, UK14,304 enhanced angiotensin II–induced intracellular superoxide (2-hydroxyethidium production) and potentiated activation of RhoA (Western blot of activated RhoA bound to the binding domain of rhotekin). The interaction between angiotensin II and UK14,304 on superoxide generation and RhoA activation was blocked by inhibitors of phospholipase C (U73312), protein kinase C (GF109203X), c-src (PP1), NADPH oxidase (diphenyleneiodonium), or superoxide (Tempol). We conclude that NADPH oxidase/superoxide and RhoA/Rho kinase are involved in the interaction between ₂-adrenoceptors and angiotensin II on renal vascular resistance by mediating signaling events downstream of the phospholipase C/protein kinase C/c-src pathway.

Key Words: phospholipase C • protein kinase C • c-src • NADPH oxidase • superoxide • RhoA • Rho kinase

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