Abstract-Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT 2 R) in pressure-natriuresis in male and female rats because AT 2 R expression has been reported to be enhanced in females.Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT 2 R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (PϽ0.001). AT 2 R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (PϽ0.01) and female (PϽ0.01) rats to a similar extent. In females, AT 2 R blockade also reduced the lower end of the autoregulatory range of renal blood flow (PϽ0.05) and glomerular filtration rate (PϽ0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT 2 R blockade. We found that AT 2 R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (PϽ0.05). In conclusion, the AT 2 R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT 2 R in renal autoregulation was evident in females, which may be a direct vascular AT 2 R effect. (Hypertension. 2011;57:275-282.)Key Words: angiotensin type 2 receptor Ⅲ gender differences Ⅲ hypertension Ⅲ natriuresis Ⅲ renal blood flow Ⅲ sodium I t is well-established that women are protected from cardiovascular and renal disease relative to men before menopause. 1 However, the mechanisms responsible for this gender difference are poorly understood, partly because females remain underrepresented in human clinical trials and animal studies. 2,3 Evidence suggests that estrogen plays a protective role against cardiovascular disease in women, 4 and previous studies have identified gender differences in the activity of the renin-angiotensin system (RAS), 1 a major regulator of arterial pressure.Studies in rodents have also revealed major gender differences in the expression of RAS components and differences in the way males and females respond to stimulation and inhibition of the RAS under physiological and pathophysiological circumstances. [5][6][7][8] Recently, with the discovery of angiotensin-converting enzyme 2, a depressor axis to the RAS has been identified 9 that incorporates the angiotensin type 2 receptor (AT 2 R), which is upregulated by estrogen. 7,10 Previously, we have demonstrated that the vasodepressor RAS pathways are enhanced in females and that the AT 2 R has a depressor influence on the response to chronic ang...

We examined the mechanisms that maintain stable renal tissue PO(2) during moderate renal ischemia, when changes in renal oxygen delivery (DO(2)) and consumption (VO(2)) are mismatched. When renal artery pressure (RAP) was reduced progressively from 80 to 40 mmHg, VO(2) (-38 ± 7%) was reduced more than DO(2) (-26 ± 4%). Electrical stimulation of the renal nerves (RNS) reduced DO(2) (-49 ± 4% at 2 Hz) more than VO(2) (-30 ± 7% at 2 Hz). Renal arterial infusion of angiotensin II reduced DO(2) (-38 ± 3%) but not VO(2) (+10 ± 10%). Despite mismatched changes in DO(2) and VO(2), renal tissue PO(2) remained remarkably stable at ≥40 mmHg RAP, during RNS at ≤2 Hz, and during angiotensin II infusion. The ratio of sodium reabsorption to VO(2) was reduced by all three ischemic stimuli. None of the stimuli significantly altered the gradients in PCO(2) or pH across the kidney. Fractional oxygen extraction increased and renal venous PO(2) fell during 2-Hz RNS and angiotensin II infusion, but not when RAP was reduced to 40 mmHg. Thus reduced renal VO(2) can help prevent tissue hypoxia during mild renal ischemia, but when renal VO(2) is reduced less than DO(2), other mechanisms prevent a fall in renal PO(2). These mechanisms do not include increased efficiency of renal oxygen utilization for sodium reabsorption or reduced washout of carbon dioxide from the kidney, leading to increased oxygen extraction. However, increased oxygen extraction could be driven by altered countercurrent exchange of carbon dioxide and/or oxygen between renal arteries and veins.

It is documented that chronic renal diseases are gender related. The protective role of angiotensin II receptor 1 (AT1) blocker losartan against cisplatin (CP)-induced nephrotoxicity was reported in males, but the role of gender is not well known. Six groups of Wistar rats were studied. Rats were divided into two groups of males and females to receive losartan for 9 days plus a single dose of CP (7 mg/kg) at day 3. Two positive control groups of males and females received the same regimen, except that they received saline instead of losartan. The negative control groups received saline instead of CP at day 3 and also saline instead of losartan. The blood samples were obtained, and the kidneys underwent histopathological investigations. All the CP-treated animals lost weight, but losartan promoted weight loss in females (p < 0.05). Coadministration of losartan and CP in females, but not in males, significantly increased the serum levels of blood urea nitrogen and creatinine when compared with the negative and positive control groups (p < 0.05). No significant differences were observed in serum levels of total proteins, magnesium, and nitrite between the groups. Administration of CP increased the kidney tissue damage score (KTDS) and normalized kidney weight (p < 0.05). However, in the presence of AT1 blockade, the KTDS (nonsignificantly) and normalized kidney weight (significantly, p < 0.05) increased in the CPtreated females. Such an observation was not seen in males. Losartan may prevent CP-induced nephrotoxicity in males, but it promotes the CP-induced damage in females, which may be related to the renin-angiotensin system receptors in the kidneys.