Physiological Significance of Angiotensin AT1A Receptors Expressed in Cells That Produce Arginine Vasopressin
Authors: Sandgren Jeremy , Linggonegoro Danny , Ni Jonathan , Claflin Kristin , Pearson Nicole , Grobe Justin 
Published: November 2023

Low‐renin and salt‐sensitive forms of hypertension are characterized by elevated secretion of arginine vasopressin (AVP). These hypertensive states are also frequently associated with elevated activity of the renin‐angiotensin system within the brain. While angiotensin II in the brain is a known stimulant of AVP secretion through its AT1 receptor, the neurocircuitry and localization of relevant AT1 receptors remains unclear. We tested the hypothesis that AT1A receptors specifically localized to AVP‐producing cells are critically involved in the regulation of AVP secretion. Co‐localization of AVP and AT1A was assessed using a dual‐fluorescent reporter approach. Mice expressing Cre‐recombinase via the AVP promoter (AVP‐Cre) were bred with mice expressing a conditional red fluorescent ROSA‐stopflox‐tdTomato construct as well as mice harboring a 206kb BAC transgene which expresses GFP via the AT1A promoter (NZ44). Dual‐fluorescent cells were detected primarily in neurons of the supraoptic nucleus (SON), while detection in the paraventricular nucleus (PVN) was negligible. Mice lacking AT1A specifically in AVP‐producing cells (AT1AAVP‐KO) were then generated by breeding AVP‐Cre mice with mice that harbor a conditional allele for the AT1A gene. At baseline, AT1AAVP‐KO mice exhibited normal serum (littermate n=13, 353±69 vs AT1AAVP‐KO n=7, 207±37 pg/mL, p=0.16) and urine (littermate n=26,145±33 vs AT1AAVP‐KO n=11, 170±54 pg/mL, p=0.68) copeptin (the stable C‐terminal fragment of AVP) despite grossly increased serum osmolality (littermate n=33, 324±1.3 vs AT1AAVP‐KO n=19, 330±1.6 mOsm/kg, p=0.007), supporting a functional role for AT1A in AVP‐producing cells. Under baseline conditions, systolic blood pressure (littermate n=18, 109±1.3 vs AT1AAVP‐KO n=5, 107±1.2 mmHg), urine volume (littermate n=27, 1.06±0.1 vs AT1AAVP‐KO n=12, 0.9±0.2 mL/d), and fluid intake (littermate n=27, 4.03±0.2 vs AT1AAVP‐KO n=12, 3.93±0.2 mL/d) were normal in AT1AAVP‐KO mice. Intake behavior was modestly altered in mice presented with a two‐bottle choice between water and escalating concentrations of NaCl (e.g. ‐water vs 0.45 M NaCl; total sodium intake: littermate n=27, 0.98±0.04 vs AT1AAVP‐KO n=12, 0.83±0.06 mEq/d, p=0.04). Blood pressure (littermate n=23, +10.35±2.1 vs AT1AAVP‐KO n=8, +12.91±2.0 mmHg), urine output (littermate n=23, +12.65±0.8 vs AT1AAVP‐KO n=9, +12.73±1.5 g/day mmHg), and fluid intake (littermate n=23, +16.17±1.3 vs AT1AAVP‐KO n=9, +14.83±2.5 mL/day) increased normally in response to deoxycorticosterone acetate‐salt challenge. Collectively these data support a role for AT1A receptors, localized specifically to AVP‐expressing cells, in the control of AVP secretion and normal osmotic regulation.Support or Funding InformationNIH T32 Pharmacological Sciences Training Program Grant (T32GM067795), University of Iowa Medical Scientist Training Program, American Heart Association (14IRG1871001), American Diabetes Association (1‐14‐BS‐079), National Institutes of Health (HL098276, HL084207)