Renal function in the AT1A receptor knockout mouse during normal and volume-expanded conditions

Background. Genetically altered mice lacking the AT(1A) angiotensin II (Ang II) receptor were used to examine the role of AT(1A) receptors in regulating renal hemodynamics, sodium excretion, glomerulotubular balance, and Ang II levels in plasma and kidney during normal and volume-expanded conditions. Methods. AT(1A) receptor-deficient mice and their wild-type controls were anesthetized with inactin and ketamine, and were prepared to allow intravenous infusions of solutions and measurements of aortic pressure and urine collections. Inulin and para-aminohippurate (PAH) solutions were infused intravenously for clearance determinations under conditions of euvolemia (2.5 mu l/min infusion of isotonic saline) or volume-expansion conditions (12.5 mu l/min). After three 30-minute urine collections, blood samples were collected, and kidneys were harvested. Plasma and kidney Ang II measurements were made by radioimmunoassay. Results. In the euvolemic state, mean arterial pressures (MAPs) were significantly lower in the AT(1A) receptor-deficient mice (68 +/- 4 mm Hg) compared with wild-type controls (89 +/- 3 mm Hg). Despite the lower MAP, the glomerular filtration rate (GFR), renal plasma how (RPF), absolute sodium excretion, and fractional sodium excretion were not significantly different between wild-type and AT(1A)-/- mice. Volume expansion did not alter MAP in wild-type mice, but significantly increased MAP in the AT(1A)-/- mice (68 +/- 4 to 83 +/- 5 mm Hg). Similar increases in GFR, RPF, absolute sodium excretion, and fractional sodium excretion in AT(1A)+/+ and AT(1A)-/- mice were observed. Glomerulotubular balance was not disrupted by the absence of AT(1A) receptors. During euvolemia, plasma Ang II concentrations were significantly higher in the AT(1A)-/- mice compared with wild-type mice (536 +/- 172 vs. 198 +/- 36 fmol/ml). Although volume expansion had no effect on plasma Ang II levels in the AT(1A)+/+ group, plasma Ang II concentrations were markedly suppressed in the AT(1A)-/- mice to levels that were not different from those in wild-type mice. In contrast, kidney tissue Ang II contents were reduced in the AT(1A)-/- mice and were not significantly altered during volume expansion in either the AT(1A)-/- or the AT(1A)+/+ mice. Conclusions. The absence of AT(1A) receptors does not impair chronic regulation of renal blood flow, GFR, or glomerulotubular balance. The prompt restoration of MAP following volume expansion suggests that low blood pressure in the AT(1A) receptor-deficient mice is primarily due to reduced effective plasma and extracellular fluid volume. Normalization of plasma Ang II levels with volume expansion demonstrates a dominant effect of extracellular fluid volume and blood pressure over AT(1A) receptor-mediated short-loop feedback in the regulation of plasma Ang II levels.