Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats.
Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats.
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DOI：
10.1161/hypertensionaha.112.192302
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Asghar M
中科院分区：
文献类型：
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作者：
Chugh G;Lokhandwala MF;Asghar M
肾多巴胺D1(D1R)和血管紧张素II 1型受体(AT1Rs)的激活影响近端肾小管钠转运体Na，K-ATPase的活性，维持钠稳态和血压。我们最近报道，在老年Fischer 344×Brown挪威F1(FBN)大鼠中，D1R功能减弱和AT1R功能过度与高血压有关，而氧化应激在这一现象中起核心作用。在这里，我们研究了与年龄相关的氧化应激增加的机制，在对照组和抗氧化剂坦普尔处理的成年和老年FBN大鼠的肾近端小管上，D1R减少和AT1R功能增加。老年γ大鼠虽然D1R数目和D1R激动剂SKF38393介导的[35S]-GTP受体结合(D1R激活指数)较低，但G蛋白偶联受体激酶4(D1R解偶联的激酶)水平较高。坦普尔治疗可恢复老年FBN大鼠D1R数和G蛋白偶联，降低G蛋白偶联受体K4水平。血管紧张素II介导的老年FBN大鼠[35S]-GTPγS结合和Na，K-ATPase活性均高于正常对照组，经坦普尔治疗后也恢复正常。我们还测量了成年和老年Fischer 344(F344)大鼠的肾脏AT1R功能，尽管它们表现出与年龄相关的氧化应激增加和肾脏D1R功能减弱，但血压正常。我们发现F344大鼠对坎地沙坦的利尿和利钠反应(AT1R功能指数)是相似的，这可能是这些大鼠没有年龄相关性高血压的原因之一。也许，D1R(减弱)和AT1R(夸大)功能的改变对于老年性高血压的发展是必要的，就像在老年FBN大鼠中看到的那样。
Activation of renal dopamine D1 (D1R) and angiotensin II type 1 receptors (AT1Rs) influences the activity of proximal tubular sodium transporter Na,K-ATPase and maintains sodium homeostasis and blood pressure. We reported recently that diminished D1R and exaggerated AT1R functions are associated with hypertension in old Fischer 344 × Brown Norway F1 (FBN) rats, and oxidative stress plays a central role in this phenomenon. Here we studied the mechanisms of age-associated increase in oxidative stress on diminished D1R and exaggerated AT1R functions in the renal proximal tubules of control and antioxidant Tempol-treated adult and old FBN rats. Although D1R numbers and D1R agonist SKF38393-mediated stimulation of [35S]-GTPγS binding (index of D1R activation) were lower, G protein– coupled receptor kinase 4 (kinase that uncouples D1R) levels were higher in old FBN rats. Tempol treatment restored D1R numbers and G protein coupling and reduced G protein– coupled receptor kinase 4 levels in old FBN rats. Angiotensin II–mediated stimulation of [35S]-GTPγS binding and Na,K-ATPase activity were higher in old FBN rats, which were also restored with Tempol treatment. We also measured renal AT1R function in adult and old Fischer 344 (F344) rats, which, despite exhibiting an age-related increase in oxidative stress and diminished renal D1R function, are normotensive. We found that diuretic and natriuretic responses to candesartan (indices of AT1R function) were similar in F344 rats, a likely explanation for the absence of age-associated hypertension in these rats. Perhaps, alterations in both D1R (diminished) and AT1R (exaggerated) functions are necessary for the development of age-associated hypertension, as seen in old FBN rats.