Absence of tubuloglomerular feedback responses in AT(1A) receptor-deficient mice

Experiments were performed in a recently generated strain of mice with an angiotensin II AT(1A)-receptor null mutation (M. Ito, M. I. Oliverio, P. J. Mannon, C. F. Best, N. Maeda, O. Smithies, and T. M. Coffman. Proc. Natl. Acad. Sci. USA 92: 3521-3525, 1995) to examine the effects of chronic AT(1A) receptor deficiency on tubuloglomerular feedback (TGF) responses. All animals were genotyped by polymerase chain reaction using primers designed to amplify sequences from the deleted AT(1A) gene and from the neomycin resistance gene. Normal mice (AT(1A) +/+) and mice heterozygous (AT(1A) +/-) and homozygous (AT(1A) -/-) for the gene disruption were anesthetized, and stop-flow pressures (P-SF) were determined during changes in loop perfusion rate with previously established micropuncture methods. In five AT(1A) +/+ mice (26 tubules) mean P-SF at zero loop flow was 37.2 +/- 1.5 mmHg, falling to 28.2 +/- 1.9 mmHg at a flow of 45 nl/min (P < 0.0001). Flow rate causing the half-maximum response (V-1/2) was 8.7 +/- 0.4 nl/min. In four AT(1A) +/- animals (19 tubules) mean PSF at zero flow was 39.9 +/- 2.4 mmHg, falling to 34.8 +/- 2.7 mmHg at 45 nl/min (mean V-1/2 8.6 +/- 1.04 nl/min). In five AT(1A) -/- mice (24 tubules) P-SF was not significantly affected by loop flow with P-SF averaging 33.9 +/- 1.7 mmHg at zero flow and 33.2 +/- 1.6 mmHg at 45 nl/min (not significant). Mean arterial blood pressures in the anesthetized and laparotomized mice were 91.8 +/- 2.2, 97.1 +/- 3, and 80.7 +/- 3.2 mmHg in the AT(1A) +/+, AT(1A) -/- and AT(1A) -/- animals, respectively. Blood pressure responses to exogenous angiotensin II were greatly blunted in the AT(1A) -/- mice. We conclude that AT(1A) receptor-mediated effects of angiotensin II are an essential component of TGF responsiveness under chronic conditions. Our studies show the feasibility of using complex micropuncture methods in mice, an approach that widens the potential of genetically altered mouse strains as experimental models.