ANG III induces expression of inducible transcription factors of AP-1 and Krox families in rat brain

In addition to rapid responses comprising increases in blood pressure, drinking, and stimulation of natriuresis, ANG II induces the expression of transcription factors (TF) in the central nervous system. The ANG II metabolite ANG III (ANG 2-8) has been demonstrated to exert physiological effects similar to those of ANG II. We aimed to determine 1) whether ANG III induces TF expression in the brain, 2) which ANG II (AT) receptor subtype is involved, and 3) whether the two peptides, ANG II and ANG III, differ in their efficacy to stimulate TF expression. ANG II (100 pmol), ANG III (100 pmol), or vehicle was injected into the lateral brain ventricle of conscious rats alone or in combination with the AT(1) receptor antagonist losartan (10 nmol), the AT(2) receptor antagonist PD-123319 (5 nmol), or the aminopeptidase inhibitor amastatin (10 nmol). Similar to ANG II, ANG III induced the expression of c-Fos, c-Jun, and Krox-24 in four brain regions, subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus of the hypothalamus, with the same efficacy. This effect was AT(1) receptor mediated. Pretreatment with amastatin reduced the expression of TF in response to ANG II, indicating that this expression is partly mediated by ANG III. Interestingly, the AT(2) receptor antagonist PD-123319 alone slightly enhanced the expression of c-Fos, c-Jun, and Krox-24 in different populations of neurons of the paraventricular nucleus. These data indicate that different populations of neurons in the paraventricular nucleus are tonically inhibited by AT(2) receptors under physiological conditions.