Compromised renal microvascular reactivity of angiotensin type 1 double null mice

Abstract

Angiotensin type 1A (AT_1A) and 1B (AT_1B) receptor deletion (AT1DKO) results in renal microvascular disease, tubulointerstitial injury, and reduced blood pressure. To test the hypothesis that renal preglomerular responses to angiotensin (ANG) II are mediated by AT_1Aand AT_1Breceptors, experiments were performed in AT1DKO mice using the in vitro blood perfused juxtamedullary nephron technique. Kidneys were harvested from AT1DKO and wild-type (WT) mice and bathed with ANG II (1–100 nM), norepinephrine (NE; 100–1,000 nM), or acetylcholine (ACh; 10 μM). Baseline diameters of afferent (19.5 ± 0.7 and 13.9 ± 0.7 μm, n = 17 and 16) and efferent (15.5 ± 2.1 and 10.8 ± 1.0 μm, n = 4 and 7) arterioles of AT1DKO were significantly larger than WT. Afferent and efferent arteriolar responses to ANG II, 100, and 300 nM NE were absent in AT1DKO; although significant constriction to 1 μM NE was observed (−17 ± 5 and −23 ± 6%, respectively). Afferent arterioles of WT mice dilated significantly in response to ACh (15.1 ± 0.6 to 17.0 ± 1.2 μm, n = 6); however, arterioles from AT1DKO tended to contract (19.9 ± 1.2 to 17.8 ± 1.6 μm; n = 6, P = 0.06). In summary, loss of ANG II-induced contraction, reduced vasoconstriction to NE, and endothelial cell dysfunction contribute to the renal vascular phenotype of AT1DKO mice. We conclude that ANG II signaling via the AT₁receptor plays a pivotal role in basal renal microvascular tone and effectiveness to respond to vasoconstrictor and vasodilator agonists.