Renal microvascular vasoconstrictor and vasodilator responses are reduced in angiotensin type 1 receptor double null mice (DKO)

Abstract

AngII induced afferent arteriolar (AA) diameter responses are reduced, while efferent arteriolar (EA) diameter responses are absent in kidneys of mice lacking the AT1A receptor compared to wild-type (WT) (AJP 284:F538-545, 2003), while responses to norepinephrine (NE) are not altered. We determined the renal microvascular reactivity of WT and DKO mice using the in vitro blood perfused juxtamedullary nephron technique. Kidneys were harvested from WT and DKO mice and bathed with NE (100–1000nM), AngII (100nM), or acetylcholine (ACh;10μM). In WT mice, AA (12.6±0.9μm; n=8) diameter was significantly reduced by 29±4 and 51±6%, and EA (11.7±0.4μm; n=8) diameter was reduced by 17±2 and 38±3% in response to 300 and 1000nM NE, respectively. Baseline AA diameters of DKO kidneys were significantly larger than WT (19.1±1.2μm; n=12), while EA diameters were not different (15.8±2.4μm; n=4). Significant constriction to 1μM NE was observed in AA and EA (18±5% AA; 23±6% EA) of kidneys from DKO mice, but were less than observed in WT mice. AngII produced a 23±7% and 28±7% reduction in AA (n=5) and EA (n=7) diameters of WT mice, respectively. Responses to AngII were absent in AA (−2±2%; n=12) and EA (−0.1±2%; n=4) of DKO mice as predicted. AA diameter increased significantly from 15.0±0.6 to 17.0±1.2μm in response to ACh in WT mice (n=6). AA diameter of DKO mice (n=6) was not significantly altered by ACh averaging 19.8±1.1 and 17.8±1.6μm (p=0.06), respectively. In summary, vasoconstrictor and vasodilator responses are reduced in renal arterioles of mice lacking both AT1A and AT1B receptor subtypes. We conclude that AngII plays a pivotal role in renal arteriolar vascular smooth muscle cell development and/or function.