Angiotensin II upregulates hypothalamic AT1 receptor expression in rats via the mitogen-activated protein kinase pathway.
ANG II type 1 receptors (AT(1)R) mediate most of the central effects of ANG II on cardiovascular function, fluid homeostasis, and sympathetic drive. The mechanisms regulating AT(1)R expression in the brain are unknown. In some tissues, the AT(1)R can be upregulated by prolonged exposure to ANG II. We examined the hypothesis that ANG II upregulates the AT(1)R in the brain by stimulating the intracellular mitogen-activated protein kinase (MAPK) signaling pathway. Using molecular and immunochemical approaches, we examined expression of the AT(1)R 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 microg/h) or saline (vehicle control), with or without concomitant (4-wk) intracerebroventricular (ICV) infusions of MAPK inhibitors or the AT(1)R blocker losartan. Subcutaneous infusion of ANG II markedly increased phosphorylation of MAPK and expression of AT(1)R mRNA and protein and AT(1)R-like immunoreactivity in the PVN and SFO. ANG II-induced AT(1)R expression was blocked by ICV infusion of the p44/42 MAPK inhibitor PD-98059 (0.025 microg/h) and the JNK inhibitor SP-600125 (0.125 microg/h), but not by the p38 MAPK inhibitor SB-203580 (0.125 microg/h). Upregulation of the AT(1)R in the PVN and SFO by peripheral ANG II was abolished by ICV losartan (10 microg/h). The data indicate that blood-borne ANG II upregulates brain AT(1)R by activating intracellular p44/42 MAPK and JNK signaling pathways.
Wei
Shun-Guang
SG
Department of Internal Medicine, Univ. of Iowa College of Medicine, E318-GH, 200 Hawkins Dr., Iowa City, IA 52242, USA.
Yu
Yang
Y
Zhang
Zhi-Hua
ZH
Felder
Robert B
RB
D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure; D006339:Heart Rate; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013356:Subfornical Organ / Q000187:drug effects / Q000201:enzymology*; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases