Blunted renal vascular response to angiotensin II is associated with a common Variant of the angiotensinogen gene and obesity
Blunted renal vascular response to angiotensin II is associated with a common Variant of the angiotensinogen gene and obesity
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DOI：
10.1097/00004872-199602000-00008
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发表时间：
1996-02-01
影响因子：
4.9
通讯作者：
Williams, GH
中科院分区：
文献类型：
--
作者：
Hopkins, PN;Lifton, RP;Williams, GH
目的 最近，我们报告了人类原发性高血压与血管紧张素原基因 (AGT) 之间的遗传联系以及与该基因的常见分子变体（蛋氨酸 235--> 苏氨酸或 T235）相关的证据。其他研究使我们推测，在高盐平衡时，肾血浆流量对输注血管紧张素 II (Ang II) 的反应减弱可能反映了肾内 Ang II 形成的增加，而这可能会促进高血压。在这里，我们研究了 AGT 基因型和肾血管对输注 Ang II 的反应之间的关系，方法对有高血压病史（年龄 18-60 岁）的高血压（n = 34，全部停止用药）和血压正常（n = 57）家庭成员以及 29 名无高血压家族史的血压正常志愿者在控制饮食 200 毫克/天钠后进行研究。以轻度加压剂量（3 ng/kg/min）输注 Ang II，并通过稳态血浆对氨基马尿酸盐浓度测定肾血浆流量。结果对多变量分析中的协变量进行校正后，T235 变异纯合子参与者对 Ang II 输注的肾血浆流量反应显着减弱 (P=0.005)，T235 纯合子中肾动脉阻力的变化也减弱。当分析仅限于正常血压参与者或根据高血压家族史细分时，发现了类似的结果， 没有发现与 AGT 基因型相关的混杂因素可以解释这些差异。此外，肥胖也会抑制肾血管对 Ang II 的反应，被发现与基因型显着相互作用 (P=0.017)，因此，在 T235 纯合子中，肥胖对肾血管反应有更大的减弱作用。 结论 在具有 AGT TT 基因型的人中，对输注 Ang II 的预期肾血管反应减弱。这是第一份关于特定基因变异与人类肾脏生理学改变之间关联的报告，特别是与原发性高血压相关。
Objective Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235-->threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a that might promote hypertension. Here we the relationship between AGT genotype and renal vascular response to infused Ang II, Methods Hypertensive (n=34, all off medication) and normotensive (n=57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly presser dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration. Results After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P=0.005), Changes in renal arterial resistance were also blunted in the T235 homozygotes, Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension, No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P=0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response,Conclusions Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.