Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel
Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel
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DOI：
10.1172/jci27546
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Capdevila, Jorge H.
中科院分区：
文献类型：
--
作者：
Nakagawa, Kiyoshi;Holla, Vijaykumar R.;Capdevila, Jorge H.
功能和生化数据表明细胞色素P450花生四烯酸单加氧酶在高血压的病理生理学中起作用，高血压是心血管、脑和肾脏发病率和死亡率的主要原因。我们在这里表明，小鼠细胞色素P450，家族4，a亚家族，多肽10(Cyp4a10)基因的破坏会导致一种类型的高血压，就像大多数人类高血压一样，对饮食盐敏感。喂食低盐饮食的Cyp4a10(-/-)小鼠血压正常，但喂食正常或高盐饮食的小鼠会变得高血压。高血压Cyp4a10(-/-)小鼠的肾脏上皮钠通道功能障碍，在给予该钠通道的选择性抑制剂阿米洛利后血压恢复正常。这些研究(A)确定了花生四烯酸单加氧酶在肾脏钠重吸收和血压调节中的生理作用，(B)证明了功能失调的Cyp4a10基因导致了肾上皮钠通道门控活性的变化，以及(C)确定了一种研究人类高血压分子基础的概念上的新方法。预计这些结果可能会为这种毁灭性疾病的早期诊断和临床治疗带来新的战略。
Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10(-/-) mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10(-/-) mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease.