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

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American Physiological Society

RESUMO

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.

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