The Role of AT1a Receptors in Angiotensin II‐induced Hypertension: No Clear Sex Differences in The Pressor Response to Angiotensin II in Male and Female Wild‐type and Proximal Tubule‐specific AT1a Receptor Knockout Mice

Abstract

Hypertension is the most important risk factor for cardiovascular, stroke, and end‐stage kidney diseases, but the mechanisms of hypertension remain incompletely understood. We reason that inappropriate activation or dysregulation of the intratubular renin‐angiotensin system in the kidney may be one of key factors in hypertension. In the present study, we generated mutant mice with proximal tubule‐specific knockout of angiotensin II (Ang II) AT1a receptors (PT‐Agtr1a−/−) in the kidney to determine whether there are significant sex differences in the pressor and natriuretic responses to Ang II. Six groups (n=8 per group) of adult male and female wild‐type and PT‐Agtr1a−/− mice were infused with Ang II via osmotic minipump for 2 weeks (40 ng/min, i.p.), and concurrently treated with or without the AT1 receptor blocker losartan (20 mg/kg/day, p.o.) to study the roles of extrarenal and proximal tubule AT1a receptors. Basal systolic blood pressure was approximately13 ± 3 mmHg lower in male and female PT‐Agtr1a−/− mice than wild‐type controls (P<0.01). Basal 24 h urinary Na+ (UNaV), K+ (UKV), and Cl− excretion (UCl−V) were all significantly higher in male and female PT‐Agtr1a−/− mice than wild‐type controls (P<0.01). In response to Ang II infusion, both male and female wild‐type and PT‐Agtr1a−/− mice developed time‐dependent hypertension, and the magnitudes of the pressor response were similar between wild‐type male (Δ43 ± 3 mmHg, P<0.01) and female (Δ44 ± 3 mmHg, P<0.01), and between male (Δ43 ± 3 mmHg, P<0.01) and female PT‐Agtr1a−/− mice (Δ39 ± 5 mmHg, P<0.01). In male wild‐type mice, 24 h UNaV increased from 139.3 ± 22.3 μmol/24 h in the time‐control group to 196.4 ± 29.6 μmol/24 h in the Ang II‐infused group (P<0.05). In female wild‐type mice, 24 h UNaV increased from 102.3 ± 12.3 μmol/24 h in the time‐control group to 173.2 ± 19.1 μmol/24 h in the Ang II‐infused group (P<0.05), respectively. In male PT‐Agtr1a−/− mice, 24 h UNaV increased from 172.0 ± 10.2 μmol/24 h in the time‐control group to 264.7 ± 35.4 μmol/24 h in the Ang II‐infused group (P<0.05). In female PT‐Agtr1a−/− mice, 24 h UNaV increased from 106.5 ± 15.0 μmol/24 h in the time‐control group to 169.1 ± 21.9 μmol/24 h in the Ang II‐infused group (P<0.05), respectively. The pressor responses to Ang II was attenuated, while the natriuretic response was promoted by concurrent treatment with losartan in male and female wild‐type and PT‐Agtr1a−/− mice (P<0.05). Taken together, we demonstrate that intratubular Ang II and AT1a receptors in the proximal tubules play a key role in maintaining normal blood pressure homeostasis and body salt and fluid balance, and that there are no significant sex differences in the pressor and natriuretic responses to Ang II in wild‐type and PT‐Agtr1a−/− mice.Support or Funding InformationThis work was supported by NIDDK grants, 2R01DK067299‐10A1 and 2R01DK102429‐03A1 to Dr. Zhuo.