Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN).
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 AT(1) and AT(2) 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)], AT(1) 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], AT(1) receptor binding was significantly lower in TG. AT(2) 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 (EC(50) = 3.1 ng) compared with SD (EC(50) = 11.2 ng), strongly suggesting that the upregulation of AT(1) 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.
Monti
J
J
Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
Schinke
M
M
Böhm
M
M
Ganten
D
D
Bader
M
M
Bricca
G
G
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism*; D001345:Autoradiography; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds; D001812:Blood-Brain Barrier / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D003919:Diabetes Insipidus / Q000235:genetics / Q000503:physiopathology; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007276:Injections, Intraventricular; D007457:Iodine Radioisotopes; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D016372:RNA, Antisense / Q000235:genetics; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000032:analysis / Q000378:metabolism*; D012492:Salts / Q000494:pharmacology; D013356:Subfornical Organ / Q000737:chemistry / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000097:blood / Q000494:pharmacology
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011725:Pyridines; D016372:RNA, Antisense; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D012492:Salts; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; C073402:PD 123319; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; C081643:candesartan