angiotensinogen and Diabetes-Insipidus

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.

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Astrocytes; Autoradiography; Benzimidazoles; Biphenyl Compounds; Blood-Brain Barrier; Brain Chemistry; Diabetes Insipidus; Drinking; Imidazoles; Injections, Intraventricular; Iodine Radioisotopes; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Antisense; Salts; Subfornical Organ; Tetrazoles; Vasoconstrictor Agents

Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Arginine Vasopressin; Blood Pressure; Brain; Cerebral Ventricles; Diabetes Insipidus; Electrolytes; Exons; Hypertension; Hypotension; Injections, Intraventricular; Organ Specificity; Rats; Renin; RNA, Antisense; RNA, Messenger; Transcription, Genetic

Angiotensinogen, the precursor of angiotensin II, was quantitated in 46 brain regions of Brattleboro rats, which lack antidiuretic hormone, and Long-Evans control rats. The regional distribution of angiotensinogen in the two strains was similar except for a small number of areas which in the Brattleboro rats displayed significant decreases; namely, lateral preoptic area, medial basal hypothalamus, medial dorsal hypothalamus, lateral hypothalamus, lateral mammillary bodies, periaquaductal gray and substantia nigra. Additionally, angiotensinogen in the posterior pituitary was significantly elevated in the Brattleboro strain. These results indicate that angiotensinogen is present in the Brattleboro rat brain and that hereditary deficiency of the ability to synthesize antidiuretic hormone may be associated with a localized alteration in angiotensinogen concentration.

Topics: Angiotensinogen; Angiotensins; Animals; Brain Chemistry; Diabetes Insipidus; Male; Rats; Rats, Brattleboro; Rats, Mutant Strains; Vasopressins

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Blood; Blood Pressure; Diabetes Insipidus; Female; Glomerular Filtration Rate; Glycerol; Hypothalamus; Osmolar Concentration; Rats; Renin; Urea