Camostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension
Camostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension
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DOI：
10.1097/hjh.0b013e328317a762
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发表时间：
2009-01-01
影响因子：
4.9
通讯作者：
Kitamura, Kenichiro
中科院分区：
文献类型：
--
作者：
Maekawa, Ai;Kakizoe, Yutaka;Kitamura, Kenichiro
前列腺素是一种糖基磷脂酰肌醇锚定的丝氨酸蛋白酶，调节上皮钠通道（ENaC）活性。钠重吸收通过ENaC在远端肾单位节段是一个限速步骤，在跨上皮钠转运。最近，前列腺素对ENaC亚基的蛋白水解切割已显示激活ENaC。因此，我们假设丝氨酸蛋白酶抑制剂可以抑制肾脏中的ENaC活性，导致血压降低。我们研究了甲磺酸卡莫司他（一种合成丝氨酸蛋白酶抑制剂）和甲磺酸卡莫司他的活性代谢产物FOY-251对小鼠皮质集合管细胞系（M-1细胞）钠转运和Dahl盐敏感大鼠血压的影响。用甲磺酸卡莫司他或FOY-251处理以剂量依赖性方式降低M-1细胞中的等效电流（I-eq），并在体外抑制前列腺素的蛋白酶活性。前列腺素基因的沉默也降低了M-1细胞中的等效电流。应用甲磺酸卡莫司他或FOY-251对M-1细胞的前列腺素蛋白的表达水平没有改变。对喂食高盐饮食的Dahl盐敏感大鼠口服给予甲磺酸卡莫司他可导致血压显著降低，尿Na/K比值升高，血清肌酐降低，尿蛋白排泄减少，以及肾损伤标志物（如胶原1、胶原3、转化生长因子β 1和nephrin）改善。这些结果表明，甲磺酸卡莫司他可能通过抑制前列腺素活性来降低M-1细胞中的ENaC活性，并且甲磺酸卡莫司他可以对Dahl盐敏感大鼠的高血压和肾损伤具有有益作用。甲磺酸卡莫司他可能是一类新的抗高血压药物，对盐敏感性高血压患者具有肾脏保护作用。J Hypertens 27：181-189（C）2009 Wolters Kluwer Health|利平科特威廉姆斯&威尔金斯。
Prostasin, a glycosylphosphatidylinositol-anchored serine protease, regulates epithelial sodium channel (ENaC) activity. Sodium reabsorption through ENaC in distal nephron segments is a rate-limiting step in transepithelial sodium transport. Recently, proteolytic cleavage of ENaC subunits by prostasin has been shown to activate ENaC. Therefore, we hypothesized that serine protease inhibitors could inhibit ENaC activity in the kidney, leading to a decrease in blood pressure. We investigated the effects of camostat mesilate, a synthetic serine protease inhibitor, and FOY-251, an active metabolite of camostat mesilate, on sodium transport in the mouse cortical collecting duct cell line (M-1 cells) and on blood pressure in Dahl salt-sensitive rats. Treatment with camostat mesilate or FOY-251 decreased equivalent current (I-eq) in M-1 cells in a dose-dependent manner and inhibited the protease activity of prostasin in vitro. Silencing of the prostasin gene also reduced equivalent current in M-1 cells. The expression level of prostasin protein was not changed by application of camostat mesilate or FOY-251 to M-1 cells. Oral administration of camostat mesilate to Dahl salt-sensitive rats fed a high-salt diet resulted in a significant decrease in blood pressure with elevation of the urinary Na/K ratio, decrease in serum creatinine, reduction in urinary protein excretion, and improvement of renal injury markers such as collagen 1, collagen 3, transforming growth factor-beta 1, and nephrin. These findings suggest that camostat mesilate can decrease ENaC activity in M-1 cells probably through the inhibition of prostasin activity, and that camostat mesilate can have beneficial effects on both hypertension and kidney injury in Dahl salt-sensitive rats. Camostat mesilate might represent a new class of antihypertensive drugs with renoprotective effects in patients with salt-sensitive hypertension. J Hypertens 27:181-189 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.