AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice

Abstract

Li XC, Shao Y, Zhuo JL. AT1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT 1a receptor-deficient mice. Am J Physiol Renal Physiol 303: F746-F756, 2012. First published June 27, 2012 doi:10.1152/ajprenal.00644.2011It is well recognized that ANG II interacts with arginine vasopressin (AVP) to regulate water reabsorption and urine concentration in the kidney. The present study used ANG II type 1a (AT 1a) receptor-deficient (Agtr1a Ϫ/Ϫ ) mice to test the hypothesis that AT 1a receptor signaling is required for basal and water deprivation-induced urine concentration in the renal medulla. Eight groups of wild-type (WT) and Agtr1a Ϫ/Ϫ mice were treated with or without 24-h water deprivation and 1-desamino-8-D-AVP (DDAVP; 100 ng/h ip) for 2 wk or with losartan (10 mg/kg ip) during water deprivation. Under basal conditions, Agtr1a Ϫ/Ϫ mice had lower systolic blood pressure (P Ͻ 0.01), greater than threefold higher 24-h urine excretion (WT mice: 1.3 Ϯ 0.1 ml vs. Agtr1a Ϫ/Ϫ mice: 5.9 Ϯ 0.7 ml, P Ͻ 0.01), and markedly decreased urine osmolality (WT mice: 1,834 Ϯ 86 mosM/kg vs. Agtr1a Ϫ/Ϫ mice: 843 Ϯ 170 mosM/kg, P Ͻ 0.01), without significant changes in 24-h urinary Na ϩ excretion. These responses in Agtr1a Ϫ/Ϫ mice were associated with lower basal plasma AVP (WT mice: 105 Ϯ 8 pg/ml vs. Agtr1a Ϫ/Ϫ mice: 67 Ϯ 6 pg/ml, P Ͻ 0.01) and decreases in total lysate and membrane aquaporin-2 (AQP2; 48.6 Ϯ 7% of WT mice, P Ͻ 0.001) and adenylyl cyclase isoform III (55.6 Ϯ 8% of WT mice, P Ͻ 0.01) proteins. Although 24-h water deprivation increased plasma AVP to the same levels in both strains, 24-h urine excretion was still higher, whereas urine osmolality remained lower, in Agtr1a Ϫ/Ϫ mice (P Ͻ 0.01). Water deprivation increased total lysate AQP2 proteins in the inner medulla but had no effect on adenylyl cyclase III, phosphorylated MAPK ERK1/2, and membrane AQP2 proteins in Agtr1a Ϫ/Ϫ mice. Furthermore, infusion of DDAVP for 2 wk was unable to correct the urine-concentrating defects in Agtr1a Ϫ/Ϫ mice. These results demonstrate that AT 1a receptor-mediated ANG II signaling is required to maintain tonic AVP release and regulate V2 receptormediated responses to water deprivation in the inner medulla. angiotensin II; angiotensin II type 1a receptor; adenylyl cyclases; aquaporin 2; arginine vasopressin; inner medullary collecting ducts; urine concentration WATER REABSORPTION by the inner medulla plays an important role in maintaining basal body electrolytes and fluid balance, urine concentration, and blood pressure homeostasis. Physiologically, water transport in the inner medulla is primarily regulated by the neuropeptide hormone arginine vasopressin ([Arg 8 ]-AVP), which is released from the posterior pituitary in response to changes in extracellular fluid volume and plasma and urine osmolality (1,23,40). In the inner medulla of the kidney, AVP binds to G s protein-coupled type 2 (V 2 ) receptors expressed on basolateral membranes of principal cells, which activates adenylyl cyclases ...

NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

“…This is consistent with the role of NFAT5 in the ANGII-mediated response to osmotic stress (32). Further, ANGII is well known both to respond to osmotic challenges and have an important role in regulating urine concentration through the AT1 receptor in the collecting duct (30,37,50). These findings in combination with our data showing Annexin-A2 expression in collecting ducts, activation by ANGII, and colocalization with AQP2 suggest that Annexin-A2 may play a role in osmotic regulation by affecting NFAT5 mRNA translation in collecting duct cells.…”

Lack of an effect of collecting duct-specific deletion of adenylyl cyclase 3 on renal Na+and water excretion or arterial pressure

“…ANG II, via ANG II type 1 (AT 1 ) receptors, stimulates cAMP production and increases AQP2 expression in cultured CD cells (18,19). Mice with either global deficiency or CD-specific KO of AT 1a receptors have impaired urinary concentrating ability (21,22,34), and inner medullary expression of both AC3 and AC6 is reduced in whole animal AT 1a KO mice (21), suggesting that ANG II may regulate both of these AC isoforms in the CD. While the present study focused on AVP-regulated CD function, future studies are needed to determine whether actions of ANG II (via the AT 1 receptor) in the CD are mediated, at least in part, through AC3 and/or AC6.…”

Role of the Na+/H+exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines

“…for 30 min before ANG II (10 pmol/min, i.v.) was infused for additional 30 min, as we described previously (Li and Zhuo 2008a;Li et al 2009Li et al , 2012b. Mice in Group 1 served as time controls.…”