Absence of tubuloglomerular feedback responses in AT1A receptor-deficient mice.

Experiments were performed in a recently generated strain of mice with an angiotensin II AT1A-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 AT1A receptor deficiency on tubuloglomerular feeback (TGF) responses. All animals were genotyped by polymerase chain reaction using primers designed to amplify sequences from the deleted AT1A gene and from the neomycin resistance gene. Normal mice (AT1A +/+) and mice heterozygous (AT1A +/-) and homozygous (AT1A -/-) for the gene disruption were anesthetized, and stop-flow pressures (PSF) were determined during changes in loop perfusion rate with previously established micropuncture methods. In five AT1A +/+ mice (26 tubules) mean PSF 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 (V1/2) was 8.7 +/- 0.4 nl/min. In four AT1A +/- 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 V1/2 8.6 +/- 1.04 nl/min). In five AT1A -/- mice (24 tubules) PSF was not significantly affected by loop flow with PSF 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 AT1A +/+, AT1A +/-, and AT1A -/- animals, respectively. Blood pressure responses to exogenous angiotensin II were greatly blunted in the AT1A -/- mice. We conclude that AT1A receptor-mediated effects of angiotensin II are in 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.

Duke Scholars

Author Thomas Myron Coffman Medicine, Nephrology