Osmolar regulation of endothelin-1 production by the inner medullary collecting duct.
Osmolar regulation of endothelin-1 production by the inner medullary collecting duct.
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DOI：
10.1016/j.lfs.2015.10.037
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发表时间：
2016-08-15
期刊：
影响因子：
6.1
通讯作者：
Kohan DE
中科院分区：
文献类型：
--
作者：
Pandit MM;Gao Y;van Hoek A;Kohan DE
内皮素-1（ET-1）是集合管（CD）Na+和水重吸收的自分泌抑制剂。高盐饮食可增加CD ET-1的产生，并在促进利钠反应中起重要作用。高盐饮食增强CD ET-1的机制正在被揭示。特别是，升高的小管流体流动，如在盐负荷中发生的，增强CD ET-1合成。高盐饮食也可改变小管液溶质含量和间质渗透压，但其对CD ET-1单独或与流量联合的影响尚不清楚。评估了小鼠内髓CD细胞系（mIMCD 3）对流量和/或渗透压变化的反应中ET-1 mRNA的产生。流量或高渗透压（使用NaCl，甘露醇或尿素）单独引起ET-1 mRNA增加约2倍，而流量和高渗透压共同增加ET-1 mRNA约14倍。单独的高渗透压效应和流量+高渗透压的协同效应被细胞内Ca 2+的螯合抑制，但是不被下游Ca 2+信号通路（钙调神经磷酸酶或NFATc）的阻断、细胞Ca 2+进入通道（嘌呤能受体或多囊蛋白-2）的抑制或上皮Na+通道的阻断所改变。用rottlerin或NFAT 5 siRNA抑制NFAT 5大大降低了单独渗透压和渗透压+流量对mIMCD 3 ET-1 mRNA水平的刺激作用。流量和渗透压单独和协同刺激mIMCD 3 ET-1 mRNA含量。这些发现可能与解释高盐饮食诱导CD ET-1产生有关。
Endothelin-1 (ET-1) is an autocrine inhibitor of collecting duct (CD) Na+ and water reabsorption. CD ET-1 production is increased by a high salt diet and is important in promoting a natriuretic response. The mechanisms by which a high salt diet enhances CD ET-1 are being uncovered. In particular, elevated tubule fluid flow, as occurs in salt loading, enhances CD ET-1 synthesis. Tubule fluid solute content and interstitial osmolality can also be altered by a high salt diet, however their effect on CD ET-1 alone, or in combination with flow, is poorly understood. ET-1 mRNA production by a mouse inner medullary CD cell line (mIMCD3) in response to changing flow and/or osmolality was assessed. Flow or hyperosmolality (using NaCl, mannitol or urea) individually caused an ~2-fold increase in ET-1 mRNA, while flow and hyperosmolality together increased ET-1 mRNA by ~14 fold. The hyperosmolality effect alone and the synergistic effect of flow + hyperosmolality was inhibited by chelation of intracellular Ca2+, however were not altered by blockade of downstream Ca2+-signaling pathways (calcineurin or NFATc), inhibition of cellular Ca2+ entry channels (purinergic receptors or polycystin-2), or blockade of the epithelial Na+ channel. Inhibition of NFAT5 with rottlerin or NFAT5 siRNA greatly reduced the stimulatory effect of osmolality alone and osmolality + flow on mIMCD3 ET-1 mRNA levels. Both flow and osmolality individually and synergistically stimulate mIMCD3 ET-1 mRNA content. These findings may be relevant to explaining high salt diet induction of CD ET-1 production.