Sex differences in angiotensin II-induced hypertension and kidney injury: role of AT1a receptors in the proximal tubule of the kidney

Abstract

Abstract In the present study, we tested the hypothesis that there are significant sex differences in angiotensin II (Ang II)-induced hypertension and kidney injury using male and female wildtype (WT) and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a−/−). Twelve groups (n=8–12 per group) of adult male and female WT and PT-Agtr1a−/− mice were infused with a pressor dose of Ang II via osmotic minipump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in the proximal tubules versus systemic tissues. Basal systolic, diastolic, and mean arterial pressure were approximately 13 ± 3 mmHg lower (P<0.01), while basal 24-h urinary Na+, K+, and Cl− excretion were significantly higher in both male and female PT-Agtr1a−/− mice than WT controls (P<0.01) without significant sex differences between different strains. Both male and female WT and PT-Agtr1a−/− mice developed hypertension (P<0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female WT and PT-Agtr1a−/− mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in both male and female PT-Agtr1a−/− mice (P<0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in both male and female WT and PT-Agtr1a−/− mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a−/− mice (P<0.01). In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without revealing significant sex differences.