血管紧张素原基因型可预测年轻高血压患者的肾血流动力学异常。

Patel Tejas V, Williams Gordon H, Fisher Naomi Deirdre L

Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

J Hypertens. 2008 Jul;26(7):1353-9. doi: 10.1097/HJH.0b013e3282ffb417.

OBJECTIVE

In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determine the interaction of age and genotype on this intermediate phenotype.

DESIGN AND METHODS

Three hundred fifteen participants had renal plasma flow response to subpressor doses of angiotensin II (3 ng/kg/min) measured by para-aminohippuric acid clearance in high-sodium balance. Individuals were divided by median age into young (<45 years) and older (> or =45 years) sets. A subset of participants was also studied after administration of captopril.

RESULTS

Age, baseline renal plasma flow, BMI and angiotensinogen 235 genotype independently predicted renal plasma flow responsiveness to angiotensin II. Renal plasma flow responses were lower in older individuals than younger (P = 0.03, hypertensive patients; P = 0.004, normotensive individuals). Both hypertensive patients and normotensive individuals carrying either angiotensinogen 235MM or MT genotypes showed this inverse association (P = 0.005, hypertensive patients; P = 0.05, normotensive individuals). However, among angiotensinogen 235TT homozygotes the pattern differed: normotensive individuals had a fall in renal vascular responsiveness with age (P = 0.01) but hypertensive patients did not (P = 0.72). Young hypertensive patients already showed blunted responses. Of all genotype subsets, only angiotensinogen 235TT hypertensive patients showed enhancement (P = 0.03) of the renal vascular responsiveness to angiotensin II after captopril.

CONCLUSION

The angiotensinogen 235TT variant predicts premature blunting of renal vascular responsiveness among young hypertensive patients. This abnormal response is corrected by angiotensin-converting enzyme inhibition. This first report of age and genotype interaction may have important implications in the profiling and management of essential hypertension.

目的

在原发性高血压患者中，肾血浆流量对血管紧张素II的反应迟钝提示肾脏中血管紧张素II病理性增加。这种反应迟钝与血管紧张素原235TT基因型有关。由于多种肾功能指标会随年龄下降，我们试图确定年龄与基因型对这种中间表型的相互作用。

设计与方法

315名参与者在高钠平衡状态下，通过对氨基马尿酸清除率测定肾血浆流量对亚升压剂量血管紧张素II（3 ng/kg/min）的反应。个体按年龄中位数分为年轻组（<45岁）和年长组（≥45岁）。部分参与者在服用卡托普利后也进行了研究。

结果

年龄、基线肾血浆流量、体重指数和血管紧张素原235基因型独立预测肾血浆流量对血管紧张素II的反应。年长个体的肾血浆流量反应低于年轻个体（高血压患者中P = 0.03；血压正常个体中P = 0.004）。携带血管紧张素原235MM或MT基因型的高血压患者和血压正常个体均表现出这种负相关（高血压患者中P = 0.005；血压正常个体中P = 0.05）。然而，在血管紧张素原235TT纯合子中情况不同：血压正常个体的肾血管反应性随年龄下降（P = 0.01），但高血压患者并非如此（P = 0.72）。年轻高血压患者已表现出反应迟钝。在所有基因型亚组中，只有血管紧张素原235TT高血压患者在服用卡托普利后肾血管对血管紧张素II的反应性增强（P = 0.03）。