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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/H1425    most recent 00942.2008v1 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 PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wei, S.-G. Articles by Felder, R. B. Search for Related Content PubMed PubMed Citation Articles by Wei, S.-G. Articles by Felder, R. B.

Angiotensin II upregulates hypothalamic AT₁ receptor expression in rats via the mitogen-activated protein kinase pathway

¹Medical Services Department of Veterans Affairs Medical Center; ²Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine; and ³Neuroscience Program, University of Iowa, Iowa City, Iowa

Submitted 25 August 2008 ; accepted in final form 5 March 2009

ANG II type 1 receptors (AT₁R) mediate most of the central effects of ANG II on cardiovascular function, fluid homeostasis, and sympathetic drive. The mechanisms regulating AT₁R expression in the brain are unknown. In some tissues, the AT₁R can be upregulated by prolonged exposure to ANG II. We examined the hypothesis that ANG II upregulates the AT₁R in the brain by stimulating the intracellular mitogen-activated protein kinase (MAPK) signaling pathway. Using molecular and immunochemical approaches, we examined expression of the AT₁R and phosphorylated MAPK in the paraventricular nucleus of the hypothalamus (PVN) and the subfornical organ (SFO) of rats receiving a chronic (4-wk) subcutaneous infusion of ANG II (0.6 µg/h) or saline (vehicle control), with or without concomitant (4-wk) intracerebroventricular (ICV) infusions of MAPK inhibitors or the AT₁R blocker losartan. Subcutaneous infusion of ANG II markedly increased phosphorylation of MAPK and expression of AT₁R mRNA and protein and AT₁R-like immunoreactivity in the PVN and SFO. ANG II-induced AT₁R expression was blocked by ICV infusion of the p44/42 MAPK inhibitor PD-98059 (0.025 µg/h) and the JNK inhibitor SP-600125 (0.125 µg/h), but not by the p38 MAPK inhibitor SB-203580 (0.125 µg/h). Upregulation of the AT₁R in the PVN and SFO by peripheral ANG II was abolished by ICV losartan (10 µg/h). The data indicate that blood-borne ANG II upregulates brain AT₁R by activating intracellular p44/42 MAPK and JNK signaling pathways.

paraventricular nucleus; subfornical organ; angiotensin II type 1 receptor; autonomic regulation