Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension
Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension
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DOI：
10.1161/hypertensionaha.116.08966
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发表时间：
2017-07-01
期刊：
影响因子：
8.3
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
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作者：
Ueda, Kohei;Nishimoto, Mitsuhiro;Fujita, Toshiro
肾钠转运系统的全基因组分析已经确定了孟德尔高血压疾病的特定变异，包括盐皮质激素明显过量的HSD 11B 2基因变异。然而，肾外组织中的这些遗传变异可能与高血压的发生有关，如先前使用全球和脑特异性Hsd 11b 2敲除啮齿动物的研究所示。为了重新检查肾功能不全对高血压发展的重要性，我们产生了肾脏特异性Hsd 11b 2基因敲除小鼠。敲除小鼠表现出全身性高血压，这是消除减少盐摄入量，表明其盐依赖性。此外，我们检测到在敲除小鼠肾细胞膜表达的裂解上皮钠通道-α和T53磷酸化Na+-Cl-协同转运蛋白的增加。与野生型对照小鼠相比，敲除小鼠急性腹腔注射阿米洛利诱导的尿钠排泄和尿钠/钾比值增加更多。长期给予阿米洛利和高氯化钾饮食显着降低平均血压的基因敲除小鼠，这是伴随着纠正低钾血症和由此产生的减少Na+-Cl-协同转运蛋白磷酸化。因此，Na+-Cl-协同转运蛋白阻断剂氢氯噻嗪显著降低基因敲除小鼠的平均血压。长期给予盐皮质激素受体拮抗剂螺内酯可显著降低基因敲除小鼠的平均血压沿着基因敲除小鼠肾脏中裂开的上皮钠通道-a和磷酸化NNa+-Cl-协同转运蛋白表达的下调。我们的数据表明，肾脏特异性缺乏11 β-HSD 2导致盐依赖性高血压，这是由于盐皮质激素受体-上皮钠通道-Na +-Cl-协同转运蛋白在肾脏中的激活，并提供证据表明，肾功能障碍是发展表观盐皮质激素过量表型所必需的。
Genome-wide analysis of renal sodium-transporting system has identified specific variations of Mendelian hypertensive disorders, including HSD11B2 gene variants in apparent mineralocorticoid excess. However, these genetic variations in extrarenal tissue can be involved in developing hypertension, as demonstrated in former studies using global and brain-specific Hsd11b2 knockout rodents. To re-examine the importance of renal dysfunction on developing hypertension, we generated kidney-specific Hsd11b2 knockout mice. The knockout mice exhibited systemic hypertension, which was abolished by reducing salt intake, suggesting its salt-dependency. In addition, we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-alpha and T53-phosphorylated Na+-Cl- cotransporter in the knockout mice. Acute intraperitoneal administration of amiloride-induced natriuresis and increased urinary sodium/potassium ratio more in the knockout mice compared with those in the wild-type control mice. Chronic administration of amiloride and high-KCl diet significantly decreased mean blood pressure in the knockout mice, which was accompanied with the correction of hypokalemia and the resultant decrease in Na+-Cl- cotransporter phosphorylation. Accordingly, a Na+-Cl- cotransporter blocker hydrochlorothiazide significantly decreased mean blood pressure in the knockout mice. Chronic administration of mineralocorticoid receptor antagonist spironolactone significantly decreased mean blood pressure of the knockout mice along with downregulation of cleaved epithelial sodium channel-a and phosphorylated NNa+-Cl- cotransporter expression in the knockout kidney. Our data suggest that kidney-specific deficiency of 11 beta-HSD2 leads to salt-dependent hypertension, which is attributed to mineralocorticoid receptor-epithelial sodium channel-Na+-Cl- cotransporter activation in the kidney, and provides evidence that renal dysfunction is essential for developing the phenotype of apparent mineralocorticoid excess.