Renal function in the AT(1A) 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 regulati ng 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 a nesthetized with inactin and ketamine, and were prepared to allow intraveno us infusions of solutions and measurements of aortic pressure and urine col lections. Inulin and para-aminohippurate (PAH) solutions were infused intra venously 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 collec ted, and kidneys were harvested. Plasma and kidney Ang II measurements were made by radioimmunoassay. Results. In the euvolemic state, mean arterial pressures (MAPs) were signif icantly lower in the AT(1A) receptor-deficient mice (68 +/- 4 mm Hg) compar ed with wild-type controls (89 +/- 3 mm Hg). Despite the lower MAP, the glo merular filtration rate (GFR), renal plasma how (RPF), absolute sodium excr etion, and fractional sodium excretion were not significantly different bet ween wild-type and AT(1A)-/- mice. Volume expansion did not alter MAP in wi ld-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 excre tion, and fractional sodium excretion in AT(1A)+/+ and AT(1A)-/- mice were observed. Glomerulotubular balance was not disrupted by the absence of AT(1 A) receptors. During euvolemia, plasma Ang II concentrations were significa ntly 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 ma rkedly suppressed in the AT(1A)-/- mice to levels that were not different f rom those in wild-type mice. In contrast, kidney tissue Ang II contents wer e reduced in the AT(1A)-/- mice and were not significantly altered during v olume expansion in either the AT(1A)-/- or the AT(1A)+/+ mice. Conclusions. The absence of AT(1A) receptors does not impair chronic regula tion of renal blood flow, GFR, or glomerulotubular balance. The prompt rest oration 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 leve ls with volume expansion demonstrates a dominant effect of extracellular fl uid volume and blood pressure over AT(1A) receptor-mediated short-loop feed back in the regulation of plasma Ang II levels.