459 A ROLE FOR ANGIOTENSIN II TYPE 1A RECEPTORS IN PRINCIPAL CELLS OF THE COLLECTING DUCT IN THE INITIATION OF HYPERTENSION

Abstract

Background: Actions of the renin-angiotensin system to control blood pressure(BP) are mediated by angiotensin type1 receptors(AT1R). The major murine AT1R isoform, AT1AR, is expressed throughout the nephron, including the dominant epithelial cell population of the collecting duct, the principal cells(PC). Between nephron segments, characteristics differ significantly resulting in distinctive regulatory consequences. Thus, this study examines the contribution of AT1AR in PC to regulation of BP. Methods: Mice lacking AT1Rs in PC(PC-KOs) were produced by intercrossing the Aqp-Cre mouse, which expresses Cre specifically in PCs with mice bearing a conditional allele for the Agtra1 gene, encoding the AT1AR. Mice were subjected to low and high-sodium diets followed by two-weeks of AngII(1000ng/kg/min) infusion via mini-osmotic pumps while BP was measured by radiotelemetry. Results: mRNA for AT1AR in inner medulla were reduced by ≈50% in PC-KO(P < 0.05). Baseline BP was identical between PC-KOs vs. controls. Following one-week of low-sodium(<0.002% NaCl) diet, MAP fell significantly(P < 0.05) and to a similar extent in both groups. Similarly, with a high-sodium(6% NaCl) diet, BP increased(P < 0.01), but was not different between groups. During first initial phase of AngII-hypertension, increase in BP was significantly attenuated in PC-KOs compared to controls(167 ± 7mmHg vs. 178 ± 3mmHg, P < 0.001). During established phase of hypertension (days 9-14), there was no significant difference in BPs between the groups. Conclusion: Our data suggests that AT1AR in principal cells of the collecting duct make a modest contribution to BP elevation in the early phase of AngII-hypertension but have negligible effects on basal BP or adaptation to changes in dietary sodium intake.