SEX DIFFERENCES IN ANGIOTENSIN II-INDUCED HYPERTENSION AND KIDNEY INJURY: ROLE OF AT1A RECEPTORS IN THE PROXIMAL TUBULE OF THE KIDNEY

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Objective: Sex differences are widely recognized to play a critical role in cardiovascular, blood pressure and renal responses to the vasoactive peptide angiotensin II (Ang II) via activation of AT1 (AT1a) receptors. However, it is not known whether there are sex differences in the pressor and renal responses to Ang II in the absence of AT1a receptors in the proximal tubules of the kidney. In the present study, we tested the hypothesis that there are significant sex differences in Ang II-induced hypertension and kidney injury using male and female wild-type and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-). Design and method: To test our hypothesis, twelve groups (n = 8–12 per group) of adult male and female wild-type and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic pump 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 extrarenal tissues or the proximal tubules of the kidney, respectively. Results: Minor sex differences were found in body wt., heart wt., or kidney wt. between male and female wild-type and PT-Agtr1a-/- mice. 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 male and female PT-Agtr1a-/- mice than wild-type controls (P < 0.01) without significant sex differences between different strains. Both male and female wild-type and PT-Agtr1a-/- mice developed time-dependent hypertension (P < 0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female wild-type and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in male and female PT-Agtr1a-/- mice (P < 0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in male and female wild-type and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P < 0.01). Conclusions: 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 significant sex differences involved.