GENDER DIFFERENCE IN MODULATION OF ANGIOTENSIN II TYPE 2 RECEPTOR (AT 2 ) FUNCTION AND EXPRESSION IN AT1A RECEPTOR‐DEFICIENT MICE

AT 2 receptor mediated renal function was examined by renal clearance and microperfusion of proximal tubules, and AT 2 receptor and ENaC expression levels were examined by real‐time PCR in the kidneys of male and female AT 1A +/+ and AT 1A −/− mice. Administration of a selective AT 2 inhibitor, PD123319, had no effect on urine volume (UV), glomerular filtration rate (GFR), and Na + excretion in both genders of AT 1A +/+ and in male AT 1A −/− mice; however, PD123319 produced significant time‐dependent diuretic and natriuretic effects in female AT 1A −/− mice. Urine volume was increased 1.2‐ and 3‐fold, ENa enhanced 1.47‐ and 2.6‐fold and FENa increased 0.66‐ and 1.4‐fold at one and two hours following bolus injection of PD123319, respectively. Microperfusion data show PD123319 produced similar effects on Na + absorption in proximal tubules of female AT 1A +/+ and AT 1A −/− mice. Real‐time PCR data show AT 2 expression in WT mice was 29% lower in females than in males (0.82 vs. 1.15); in AT 1A −/− mice, it was increased by 79% (from 0.82 to 1.47) in females but reduced by 70% (from 1.15 to 0.35) in males. α, β and γ‐ENaC expression levels were 30%, 50% and 25% higher, respectively, in females compared to male AT 1A +/+ mice. They were reduced by 20%, 22% and 32% in male null mice, but not changed in female null mice compared to the WT. There were no increases in expression levels of other ion transporters (NHE3, NCC and NKCC2) in AT 1A −/− mice. We conclude that the elevated AT 2 receptor and ENaC expression in the kidney may be responsible for AT 2 ‐mediated Na + and water retention in female AT 1A −/− mice.