Abstract 42: AT1 Angiotensin Receptors in Principal Cells of the Collecting Duct Have Minimal Impact on Blood Pressure and the Development of Hypertension.
The main actions of the renin angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT1R). The major murine AT1R isoform, AT1A is highly expressed in epithelial cells throughout the nephron, including the collecting duct (CD). The CD consists of two cell types, principal (PC) and intercalated cells (IC) with distinct functions. Activation of AT1R in PC stimulates solute reabsorption in the CD by increasing the activity of epithelial sodium channels. To examine the role of the AT1AR in the PC to BP regulation and the development of hypertension in vivo, we generated inbred 129SvEv mice with cell-specific deletion of AT1AR in PC (PC-KO, n=6). AQP2-Cre transgenic mouse line was used to excise the floxed Agtr1a allele in PC. mTmG reporter mouse line was used to confirm specific expression of AQP2-Cre transgene in PC, and found the pattern of expression to be predominantly in medullary CD. Using RT-PCR, mRNA levels for AT1AR were reduced by ≈50% in the inner medulla of PC-KO mice (P<0.05), but unaffected in cortex. Baseline BP measured by radiotelemetry was similar between PC-KO (122±1.6 mm Hg) and controls (122±1.6 mm Hg). During one week of feeding a low salt (<0.002% NaCl) diet, MAP fell significantly (P<0.05) and to a similar extent in both groups, (PC-KO: 116±1 mm Hg; Controls: 117±2 mm Hg). High salt (6% NaCl) diet increased BP (P<0.01), but was not different between groups (PC-KO: 129±2 mm Hg; Controls: 131±2 mm Hg). Finally, we induced hypertension with chronic infusion of Ang II (1000 ng/kg/min) by osmotic mini-pumps. During the initial phase (days 1-8), there was a modest but significant attenuation of hypertension in PC-KO (167±7 mm Hg) compared to controls (178±3 mm Hg, P<0.001). However, by day 9 levels of BP were indistinguishable between groups and there was no difference in BP in the later phase (days 9-14) of hypertension (PC-KO: 175±12 mm Hg; Controls: 177±7 mm Hg). Heart to body weight ratio after Ang II infusion was not different between groups. In summary, AT1AR in PC of the medullary CD have little influence on BP, adaptation to changes in dietary salt intake or development of hypertension. We suggest that other mediators, such as aldosterone, may have a more important role to influence sodium handling in this nephron segment.
- © 2012 by American Heart Association, Inc.