Camostat mesilate, a serine protease inhibitor, exerts aquaretic effects and decreases urinary exosomal AQP2 levels
Camostat mesilate, a serine protease inhibitor, exerts aquaretic effects and decreases urinary exosomal AQP2 levels
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DOI：
10.1016/j.jphs.2022.09.003
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发表时间：
2022-10-05
影响因子：
3.5
通讯作者：
Mukoyama，Masashi
中科院分区：
文献类型：
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作者：
Kakizoe，Yutaka;Nakagawa，Terumasa;Mukoyama，Masashi
丝氨酸蛋白酶（SP）在肾脏中发挥生理作用。我们以前报道，合成的SP抑制剂，卡莫司他甲磺酸盐（CM），抑制钠在肾小管重吸收，并显示在醛固酮输注大鼠的利钠作用。在这里，我们的目的是探索新的生理作用的SP在肾小管和了解的作用机制的SP抑制剂，通过管理CM健康大鼠。将Sprague-Dawley大鼠分为对照组和CM（皮下缓释丸）组，并在第7天处死。CM以尿钠和渗透压物质排泄非依赖性方式显著增加尿量约2倍，表明发生游离水排泄。CM给药后，血清加压素、钾和钙水平以及肾髓质中的渗透压（均影响肾小管中游离水的重吸收）保持不变。CM减少尿外泌体AQP 2排泄，表明集合管中AQP 2活性的抑制。去氨加压素可逆转这些变化。CM引起的水利尿作用与其对前列腺素或TMPRSS 4的作用无关。我们的研究结果揭示了SP抑制与自由水处理的关联，并表明CM给药具有利尿作用，AQP 2下调，表明SP抑制剂作为一类新的利尿药物。
Serine proteases (SPs) play physiological roles in the kidney. We previously reported that a synthetic SP inhibitor, camostat mesilate (CM), suppressed sodium reabsorption in the renal tubule and showed natriuretic effects in aldosterone-infused rats. Here, we aimed to explore novel physiological roles of SPs in the renal tubule and understand the mechanism of actions of SP inhibitors, by administering CM to healthy rats. Sprague–Dawley rats were classified into control and CM (subcutaneous sustained-release pellet) groups and sacrificed on day 7. CM significantly increased urine volumes by approximately two-fold in a urinary sodium- and osmolyte excretion-independent manner, indicating the occurrence of free water excretion. Serum vasopressin, potassium, and calcium levels and the osmolality in the renal medulla, which all affect free water reabsorption in the renal tubule, remained unchanged after CM administration. CM decreased urinary exosomal AQP2 excretion, suggesting suppression of AQP2 activity in the collecting duct. These changes were reversed by desmopressin infusion. Water diuresis caused by CM was independent of its action on prostasin or TMPRSS4. Our results revealed the association of SP inhibition with free water handling and demonstrated that CM administration exerted diuretic effects with AQP2 downregulation, suggesting SP inhibitors as a new class of aquaretic drugs.