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Am J Physiol Regul Integr Comp Physiol 280: R233-R240, 2001;
0363-6119/01 $5.00
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Vol. 280, Issue 1, R233-R240, January 2001

Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN)

Jan Monti1,2, Martina Schinke1, Manfred Böhm1, Detlev Ganten1,3, Michael Bader1, and Giampiero Bricca1,2

1 Max Delbrück Center for Molecular Medicine, 13092 Berlin; 3 Department of Clinical Pharmacology, University Hospital Benjamin Franklin, Free University Berlin, 12200 Berlin, Germany; and 2 Institut National de la Santé et de la Recherche Médicale Unité 331, 69675 Bron, France

TGR(ASrAOGEN)680, a newly developed transgenic rat line with specific downregulation of astroglial synthesis of angiotensinogen, exhibits decreased brain angiotensinogen content associated with a mild diabetes insipidus and lower blood pressure. Autoradiographic experiments were performed on TGR(ASrAOGEN) (TG) and Sprague-Dawley (SD) control rats to quantify AT1 and AT2 receptor-binding sites in different brain nuclei and circumventricular organs. Dose-response curves for drinking response to intracerebroventricular injections of ANG II were compared between SD and TG rats.

In most of the regions inside the blood-brain barrier [paraventricular nucleus (PVN), piriform cortex, lateral olfactory tract (LOT), and lateral preoptic area (LPO)], AT1 receptor binding (sensitive to CV-11974) was significantly higher in TG compared with SD. In contrast, in the circumventricular organs investigated [subfornical organ (SFO) and area postrema], AT1 receptor binding was significantly lower in TG. AT2 receptors (binding sensitive to PD-123319) were detected at similar levels in the inferior olive (IO) of both strains. Angiotensin-binding sites sensitive to both CV-11974 and PD-123319 were detected in the LPO of SD rats and specifically upregulated in LOT, IO, and most notably PVN and SFO of TG. The dose-response curve for water intake after intracerebroventricular injections showed a higher sensitivity to ANG II of TG (EC50 = 3.1 ng) compared with SD (EC50 = 11.2 ng), strongly suggesting that the upregulation of AT1 receptors inside the blood-brain barrier of TG rats is functional.

Finally, we showed that downregulation of angiotensinogen synthesized by astroglial cells differentially regulates angiotensin receptor subtypes inside the brain and in circumventricular organs.

antisense; angiotensin receptor subtypes


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