Na delivery and ENaC mediate flow regulation of collecting duct endothelin-1 production.
Na delivery and ENaC mediate flow regulation of collecting duct endothelin-1 production.
复制标题
Na 输送和 ENaC 介导集合管内皮素 1 产生的流量调节。
DOI：
10.1152/ajprenal.00034.2012
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Kohan,DonaldE
中科院分区：
文献类型：
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作者：
Pandit,MeghanaM;Strait,KevinA;Matsuda,Toshio;Kohan,DonaldE
集合管(CD)内皮素-1(ET-1)是一种重要的钠和水运输自分泌抑制物。CD-ET-1的产生受到细胞外液体积膨胀和小管液流动的刺激，提示CD-Na转运和ET-1合成是耦合的机制。小鼠皮质CD细胞系mpkCCDC14在2dyn/cm2的静态或流动条件下作用2 h，然后测定ET-1mRNA的含量。300momoL/L的氯化钠使ET-1mRNA的表达增加到静态条件下的65%。灌流液渗透压升高至450momoL/L时，加入氯化钠或醋酸钠可使ET-1m RNA的∼增加184%，而加入甘露醇或尿素则无此作用。用尿素或甘露醇将钠浓度降至150momoL/L，同时将总渗透压维持在300momoL/L，则可降低血流反应。用阿米洛利或苯扎米抑制上皮钠通道(ENaC)可消除这种流动反应，提示ENaC参与了血流调节的ET-1合成。醛固酮几乎是流动反应的两倍。由于Ca~(2+)促进CD-ET-1的产生，因此对质膜和线粒体Na/Ca~(2+)交换器(NCX)的参与进行了评估。质膜NCX抑制剂SEA0400和KB-R7943不影响流量反应。然而，线粒体NCX抑制剂CGP37157取消了这种反应。综上所述，目前的研究表明，增加Na的供应，导致ENaC介导的Na进入和线粒体NCx活性，参与了血流刺激的CD ET-1的合成。这是首次报道ENaC或线粒体NCX调控生物系统中的自分泌因子。
Collecting duct (CD) endothelin-1 (ET-1) is an important autocrine inhibitor of Na and water transport. CD ET-1 production is stimulated by extracellular fluid volume expansion and tubule fluid flow, suggesting a mechanism coupling CD Na delivery and ET-1 synthesis. A mouse cortical CD cell line, mpkCCDc14, was subjected to static or flow conditions for 2 h at 2 dyn/cm2, followed by determination of ET-1 mRNA content. Flow with 300 mosmol/l NaCl increased ET-1 mRNA to 65% above that observed under static conditions. Increasing perfusate osmolarity to 450 mosmol/l with NaCl or Na acetate increased ET-1 mRNA to ∼184% compared with no flow, which was not observed when osmolarity was increased using mannitol or urea. Reducing Na concentration to 150 mosmol/l while maintaining total osmolarity at 300 mosmol/l with urea or mannitol decreased the flow response. Inhibition of epithelial Na channel (ENaC) with amiloride or benzamil abolished the flow response, suggesting involvement of ENaC in flow-regulated ET-1 synthesis. Aldosterone almost doubled the flow response. Since Ca2+enhances CD ET-1 production, the involvement of plasma membrane and mitochondrial Na/Ca2+exchangers (NCX) was assessed. SEA0400 and KB-R7943, plasma membrane NCX inhibitors, did not affect the flow response. However, CGP37157, a mitochondrial NCX inhibitor, abolished the response. In summary, the current study indicates that increased Na delivery, leading to ENaC-mediated Na entry and mitochondrial NCX activity, is involved in flow-stimulated CD ET-1 synthesis. This constitutes the first report of either ENaC or mitochondrial NCX regulation of an autocrine factor in any biologic system.