Li Ningjun
Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University Richmond, VA 23298.
Am J Cardiovasc Dis. 2012;2(3):208-15. Epub 2012 Jul 25.
Many enzymes that produce natriuretic factors such as nitric oxide synthase (NOS), hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) are highly expressed in the renal medulla. These enzymes in the renal medulla are up-regulated in response to high salt intake. Inhibition of these enzymes within the renal medulla reduces sodium excretion and increases salt sensitivity of arterial blood pressure, indicating that these enzymes play important roles in kidney salt handling and renal adaptation to high salt challenge. However, it remains a question what mechanisms mediate the activation of these enzymes in response to high salt challenge in the renal medulla. Interestingly, these enzymes are oxygen sensitive genes and regulated by transcription factor hypoxia-inducible factor (HIF)-1α. Our recent serial studies have demonstrated that: 1) High salt intake stimulates HIF-1α-mediated gene expression, such as NOS, HO-1 and COX-2, in the renal medulla, which may augment the production of different antihypertensive factors in the renal medulla, mediating renal adaptation to high salt intake and regulating salt sensitivity of arterial blood pressure. 2) HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, is highly expressed in renal medulla. High salt intake suppresses the expression of PHD2 in the renal medulla, which increases HIF-1α-mediated gene expressions in the renal medulla, thereby participates in the control of salt sensitivity of blood pressure. 3) The high salt-induced inhibition in PHD2 and the consequent activation of HIF-1α in the renal medulla is not observed in Dahl salt sensitive hypertensive (Dahl/ss) rats. Correction of these defects in PHD2/HIF-1α-associated molecular adaptation in the renal medulla improves sodium excretion, reduces sodium retention and attenuates saltsensitive hypertension in Dahl/ss rats. In conclusion, PHD2 regulation of HIF-1α-mediated gene activation in the renal medulla is an important molecular adaptation to high salt intake; impaired PHD2 regulation of HIF-1α-mediated gene activation in the renal medulla may be responsible for the salt-sensitive hypertension in Dahl/ss rats; correction of these defects may be used to as therapeutic strategies for the treatment of salt-sensitive hypertension.
许多产生利钠因子的酶，如一氧化氮合酶（NOS）、血红素加氧酶-1（HO-1）和环氧化酶-2（COX-2），在肾髓质中高度表达。肾髓质中的这些酶会因高盐摄入而上调。抑制肾髓质中的这些酶会减少钠排泄并增加动脉血压的盐敏感性，这表明这些酶在肾脏盐处理和肾脏对高盐挑战的适应性中发挥重要作用。然而，在肾髓质中，是什么机制介导这些酶对高盐挑战的激活仍是一个问题。有趣的是，这些酶是氧敏感基因，受转录因子缺氧诱导因子（HIF）-1α调控。我们最近的系列研究表明：1）高盐摄入刺激肾髓质中HIF-1α介导的基因表达，如NOS、HO-1和COX-2，这可能会增加肾髓质中不同降压因子的产生，介导肾脏对高盐摄入的适应性并调节动脉血压的盐敏感性。2）HIF脯氨酰羟化酶2（PHD2），一种促进HIF-1α降解的酶，在肾髓质中高度表达。高盐摄入会抑制肾髓质中PHD2的表达，这会增加肾髓质中HIF-1α介导的基因表达，从而参与血压盐敏感性的控制。3）在 Dahl 盐敏感高血压（Dahl/ss）大鼠中未观察到高盐诱导的肾髓质中PHD2抑制及随后的HIF-1α激活。纠正肾髓质中PHD2/HIF-1α相关分子适应性的这些缺陷可改善钠排泄，减少钠潴留并减轻Dahl/ss大鼠的盐敏感性高血压。总之，肾髓质中PHD2对HIF-1α介导的基因激活的调节是对高盐摄入的重要分子适应性；肾髓质中PHD2对HIF-1α介导的基因激活的调节受损可能是Dahl/ss大鼠盐敏感性高血压的原因；纠正这些缺陷可作为治疗盐敏感性高血压的治疗策略。
