Loss of Biphasic Effect on Na/K-ATPase Activity by Angiotensin II Involves Defective Angiotensin Type 1 Receptor-Nitric Oxide Signaling
Loss of Biphasic Effect on Na/K-ATPase Activity by Angiotensin II Involves Defective Angiotensin Type 1 Receptor-Nitric Oxide Signaling
复制标题
DOI：
10.1161/hypertensionaha.108.117911
复制
发表时间：
2008-12-01
期刊：
影响因子：
8.3
通讯作者：
Lokhandwala, Mustafa F.
中科院分区：
文献类型：
--
作者：
Banday, Anees Ahmad;Lokhandwala, Mustafa F.
氧化应激会导致血管紧张素 (Ang) 1 型受体 (AT1R) 功能发生变化，从而导致高血压。 Ang II 通过影响 Na/K-ATP 酶 (NKA) 来调节肾 Na+ 吸收，从而维持钠稳态，从而影响血压。在低浓度下，Ang II 会刺激 NKA；较高浓度会抑制该酶。我们研究了氧化应激对参与 NKA 双相调节的肾 AT1R 功能的影响。雄性 Sprague-Dawley 大鼠接受自来水（对照）和 30 mmol/L L-丁硫氨酸亚砜亚胺 (BSO)（一种氧化剂），并添加或不添加 1 mmol/L Tempol（抗氧化剂），为期 2 周。 BSO 治疗的大鼠表现出氧化应激增加、AT1R 上调和高血压。在对照大鼠的近端肾小管中，Ang II 对 NKA 活性产生双相作用，导致皮摩尔浓度下酶的刺激和微摩尔浓度下的抑制。然而，在 BSO 处理的大鼠中，Ang II 在两种浓度下都会刺激 NKA。 Ang II 的作用被 AT1R 拮抗剂坎地沙坦和丝裂原激活蛋白激酶抑制剂 UO126 消除，而 Ang 2 型受体拮抗剂 PD-123319 和 NO 合酶抑制剂 NG-硝基-L-精氨酸甲酯则没有作用。 Ang II 的抑制作用对坎地沙坦和 NG-硝基-L-精氨酸甲酯敏感，而 PD-123319 和 UO126 无影响。在 BSO 处理的大鼠中，Ang II 显示出对 NKA、丝裂原激活蛋白激酶、富含脯氨酸的酪氨酸激酶 2 和 NADPH 氧化酶的过度刺激，但未能激活 NO 信号传导。 Tempol 可以减少氧化应激，使 AT1R 信号正常化，揭示对 NKA 的双相作用，并降低 BSO 治疗大鼠的血压。总之，氧化应激介导的 AT1R 上调导致 NKA 双相反应丧失和高血压。 Tempol 使 AT1R 信号和血压正常化。 （高血压。2008；52：1099-1105。）
Oxidative stress causes changes in angiotensin (Ang) type 1 receptor (AT1R) function, which contributes to hypertension. Ang II affects blood pressure via maintenance of sodium homeostasis by regulating renal Na+ absorption through its effects on Na/K-ATPase (NKA). At low concentrations, Ang II stimulates NKA; higher concentrations inhibit the enzyme. We examined the effect of oxidative stress on renal AT1R function involved in biphasic regulation of NKA. Male Sprague-Dawley rats received tap water (control) and 30 mmol/L of L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mmol/L of Tempol (antioxidant) for 2 weeks. BSO-treated rats exhibited increased oxidative stress, AT1R upregulation, and hypertension. In proximal tubules from control rats, Ang II exerted a biphasic effect on NKA activity, causing stimulation of the enzyme at picomolar and inhibition at micromolar concentrations. However, in BSO-treated rats, Ang II caused stimulation of NKA at both of the concentrations. The effect of Ang II was abolished by the AT1R antagonist candesartan and the mitogen-activated protein kinase inhibitor UO126, whereas the Ang type 2 receptor antagonist PD-123319 and NO synthase inhibitor NG-nitro-L-arginine methyl ester had no effect. The inhibitory effect of Ang II was sensitive to candesartan and NG-nitro-L-arginine methyl ester, whereas PD-123319 and UO126 had no effect. In BSO-treated rats, Ang II showed exaggerated stimulation of NKA, mitogen-activated protein kinase, proline-rich-tyrosine kinase 2, and NADPH oxidase but failed to activate NO signaling. Tempol reduced oxidative stress, normalized AT1R signaling, unmasked the biphasic effect on NKA, and reduced blood pressure in BSO-treated rats. In conclusion, oxidative stress-mediated AT1R upregulation caused a loss of NKA biphasic response and hypertension. Tempol normalized AT1R signaling and blood pressure. (Hypertension. 2008; 52: 1099-1105.)