Control of renal Na+ excretion by heme oxygenase.
Control of renal Na+ excretion by heme oxygenase.
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血红素加氧酶控制肾钠排泄。
DOI：
10.1161/01.hyp.0000250089.99513.f6
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Pallone,ThomasL
中科院分区：
文献类型：
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作者：
Pallone,ThomasL
在本期《高血压》中，Li 等人提供的证据支持肾髓质血红素加氧酶 (HO) 在肾脏调节盐和水排泄中的急性和慢性作用。 1 他们的研究结果可概括如下：HO 活性和表达随髓轴升高；内髓质 外髓质 皮质。肾灌注压 (RPP) 急性升高会导致髓质组织中一氧化碳 (CO) 和 NO 浓度升高，并伴有尿钠排泄。铬中卟啉 (CrMP) 抑制髓质匀浆的 H2O 活性，当注入肾间质时，可降低基础和 RPP 刺激的 CO、NO 水平以及盐和水的排泄。 Li 及其同事通过检查维持 1% 或 8% NaCl 饮食的大鼠体内 CrMP 的慢性间质输注，使他们的研究向前迈出了重要的一步。那些接受 1% 氯化钠饮食的人在 1 周内经历了短暂的平均动脉压升高 5 至 10 毫米汞柱。相比之下，在 8% NaCl 饮食中，CrMP 引起持续且令人印象深刻的升高 25 至 30 毫米汞柱。最后，高盐饮食增加了诱导型 HO-1 的表达和活性，但不增加 HO-2。基础 H2O 阻断的有效性显示了血红素降解产物对上皮 Na 重吸收的补强作用。此外，CrMP 抑制 H2O2 会减弱与 RPP 急剧增加相关的利尿和尿钠排泄；它可以阻止“压力尿钠”（图）。这些基本发现指出了 H2O 在调节 Na 平衡中的重要性，并提出了许多问题。什么途径将 RPP 与 HO 活性连接起来？ H2O如何促进盐和水的排泄并影响血压？这些发现为压力性尿钠排泄的机制提供了哪些见解？由于 H2O 产物是由血红素降解产生的，是否存在增加该底物可用性的途径？ H2O 的众多功效可追溯到其产品的抗氧化和血管舒张特性。 2–4 还原 O2 产生活性氧 (ROS)，包括超氧阴离子 (O2) 和过氧化氢 (H2O2)，进而产生次氯酸和羟基自由基。 O2 消耗一氧化氮，降低其作为血管舒张剂的可用性，产生过氧亚硝酸盐，这是一种通过蛋白质亚硝基化产生独立有害作用的物质。 ROS 通过内源途径产生，包括线粒体氧化磷酸化、各种 O2 利用酶的活性、半胱氨酸的自氧化、NO 合酶的底物限制活性，也许最重要的是，通过 NADPH 氧化酶的调节活性。去除 ROS 的抗氧化系统包括将 O2 转化为 H2O2 的超氧化物歧化酶 (SOD) 和将 H2O2 转化为水的过氧化氢酶。维生素 C 和 E 等自由基清除剂也会限制 ROS。在后一种情况下，H2O 通过产生内源性抗氧化剂胆红素，已被认为发挥着重要作用。除了对盐和水排泄的影响外，肾脏 HO-1 活性还有利于防止缺血再灌注损伤、3 种炎症性疾病和移植排斥。 4HO-1 和 HO-2 分别是受调节的微粒体酶和组成型线粒体酶，可降解血红素形成 CO 和胆绿素。 CO 与 NO 一样，通过 cGMP 发出信号以促进血管舒张和排尿。胆绿素通过胆绿素还原剂转化为胆红素，胆红素是一种有效的 ROS 清除剂。胆红素通过抑制 NADPH 氧化酶和蛋白激酶 C 的活性发挥进一步的抗氧化作用。在肾髓质中，HO-1 受到缺氧诱导因子 α1 (HIF1α) 的转录控制，如……
In the current issue of Hypertension, Li et al provide evidence that supports acute and chronic roles for renal medullary heme oxygenase (HO) in the regulation of salt and water excretion by the kidney. 1 Their findings may be summarized as follows: HO activity and expression rises with medullary axis; inner medulla outer medulla cortex. Acute elevation of renal perfusion pressure (RPP) induces a rise in the medullary tissue carbon monoxide (CO) and NO concentrations accompanied by natriuresis. Chromium mesoporphyrin (CrMP) inhibits the HO activity of medullary homogenates and, when infused into the renal interstitium, reduces both basal-and RPP-stimulated CO, NO levels, and salt and water excretion. Li and colleagues carried their investigation an important step further by examining chronic interstitial infusion of CrMP in rats maintained on either a 1% or 8% NaCl diet. Those on a 1% NaCl diet experienced a transient, 1-week elevation of mean arterial pressure of 5 to 10 mmHg. By comparison, on an 8% NaCl diet, CrMP induced a sustained and impressive rise of 25 to 30 mm Hg. Finally, expression and activity of inducible HO-1 but not HO-2 was increased by the high salt diet. The effectiveness of basal HO blockade shows a tonic effect of the products of heme degradation on epithelial Na reabsorption. Moreover, HO inhibition by CrMP blunts the diuresis and natriuresis associated with an acute increase in RPP; it blocks “pressure natriuresis”(Figure). These fundamental findings point to the importance of HO in the regulation of Na balance and raise many questions. What pathway connects RPP to HO activity? How does HO enhance salt and water excretion and affect blood pressure? What insights do these findings provide into the mechanisms that underlie pressure natriuresis? Because HO products arise from heme degradation, do pathways exist that increase availability of that substrate? The myriad effects of HO have been traced to the antioxidant and vasodilatory properties of its products. 2–4 Reduction of O2 yields reactive oxygen species (ROS) including superoxide anion (O2) and hydrogen peroxide (H2O2), which, in turn generate hypochlorous acid and hydroxyl radicals. O2 consumes NO, reducing its availability as a vasodilator, producing peroxynitrite, a species that has independent injurious effects through protein nitrosylation. ROS are generated by endogenous pathways, including mitochondrial oxidative phosphorylation, activities of various O2-utilizing enzymes, auto-oxidation of cysteine, substrate limited activity of NO synthase, and, perhaps most importantly, through the regulated activity of NADPH oxidase. Antioxidant systems that remove ROS include superoxide dismutases (SOD), which converts O2 to H2O2, and catalase that convert H2O2 to water. Free radical scavengers such as vitamin C and E also limit ROS. In the latter context, HO, through its generation of the endogenous antioxidant bilirubin, has been recognized to play a prominent role. In addition to effects on salt and water excretion, renal HO-1 activity favors protection from ischemia-reperfusion injury, 3 inflammatory diseases, and transplant rejection. 4HO-1 and HO-2 are regulated microsomal and constitutive mitochondrial enzymes, respectively, that degrade heme to form CO and biliverdin. CO, like NO, signals through cGMP to favor vasodilation and saliuresis. Biliverdin is converted by biliverdin reductace to bilirubin, an effective ROS scavenger. Bilirubin exerts further antioxidant effects by inhibiting the activities of NADPH oxidase and protein kinase C. In the renal medulla, HO-1 is under the transcriptional control of hypoxia inducible factor α1 (HIF1α), as …