Sexual Dimorphism in Urinary Angiotensinogen Excretion During Chronic Angiotensin II−Salt Hypertension

Vicky F. Rands PhD , Dale M. Seth MS , Hiroyuki Kobori MD, PhD , Minolfa C. Prieto MD, PhD
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引用次数: 24

Abstract

Background

The intrarenal renin−angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin−angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females.

Objective

This study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)−dependent hypertension and high-salt (HS) diet.

Methods

Male and female Sprague-Dawley rats were divided into 5 groups for each sex: Normal-salt control, HS diet (8% NaCl), Ang II−infused (80 ng/min), Ang II−infused plus HS diet, and Ang II−infused plus HS diet and treatment with the Ang II receptor blocker, candesartan (25 mg/L in the drinking water). Rats were evaluated for systolic blood pressure (SBP), kidney AGT mRNA expression, urinary AGT excretion, and proteinuria at different time points during a 14-day protocol.

Results

Both male and female rats exhibited similar increases in urinary AGT, with increases in SBP during chronic Ang II infusion. HS diet greatly exacerbated the urinary AGT excretion in Ang II−infused rats; males had a 9-fold increase over Ang II alone and females had a 2.5-fold increase. Male rats displayed salt-sensitive SBP increases during Ang II infusion and HS diet, and female rats did not. In the kidney cortex, males displayed greater AGT gene expression than females during all treatments. During Ang II infusion, both sexes exhibited increases in AGT gene message compared with same-sex controls. In addition, HS diet combined with Ang II infusion exacerbated the proteinuria in both sexes. Concomitant Ang II receptor blocker treatment during Ang II infusion and HS diet decreased SBP and urinary AGT similarly in both sexes; however, the decrease in proteinuria was greater in the females.

Conclusion

During Ang II−dependent hypertension and HS diet, higher intrarenal renin-angiotensin system activation in males, as reflected by higher AGT gene expression and urinary excretion, indicates a mechanism for greater progression of high blood pressure and might explain the sex disparity in development of salt-sensitive hypertension.

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慢性血管紧张素II−盐高血压患者尿血管紧张素原排泄的性别二态性
肾内肾素-血管紧张素系统通过调节整个肾单位的钠和水的重吸收来参与高血压。肾素-血管紧张素系统的肾内成分的性别差异与男性比女性更容易患高血压和进展为肾损害有关。目的探讨血管紧张素II (angii)依赖性高血压和高盐饮食(HS)中血管紧张素原(AGT)的肾内基因表达和尿排泄是否存在性别差异。方法将雄性和雌性sd大鼠按性别分为5组:正常盐对照、HS饮食(8% NaCl)、注入Ang II−(80 ng/min)、注入Ang II−加HS饮食、注入Ang II−加HS饮食并给予Ang II受体阻滞剂坎地沙坦(25 mg/L,饮用水中)。在14天的研究过程中,评估大鼠在不同时间点的收缩压(SBP)、肾脏AGT mRNA表达、尿AGT排泄和蛋白尿。结果雄性和雌性大鼠均表现出相似的尿AGT升高,慢性输注Ang II时SBP升高。HS饮食显著促进了angii−输注大鼠尿中AGT的排泄;雄性比单独的Ang II增加了9倍,雌性增加了2.5倍。雄性大鼠在注射Ang II和HS饮食时表现出盐敏感的收缩压升高,而雌性大鼠则没有。在肾皮质中,在所有治疗过程中,男性表现出比女性更高的AGT基因表达。在Ang II输注期间,与同性对照相比,两性都表现出AGT基因信息的增加。此外,HS饮食联合angii输注加重了男女蛋白尿。在输注Ang II和HS饮食期间,同时使用Ang II受体阻滞剂可降低男女的收缩压和尿AGT;然而,蛋白尿的减少在女性中更大。结论在angii−依赖性高血压和HS饮食过程中,男性肾内肾素-血管紧张素系统的高激活,通过AGT基因的高表达和尿排泄来反映,这可能是高血压更大进展的机制,并可能解释盐敏感性高血压发展的性别差异。
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Gender Medicine
Gender Medicine 医学-医学:内科
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