Adenosine activates a2b receptors and enhances chloride secretion in kidney inner medullary collecting duct cells.
Adenosine activates a2b receptors and enhances chloride secretion in kidney inner medullary collecting duct cells.
复制标题
腺苷激活 a2b 受体并增强肾内髓质集合管细胞的氯化物分泌。
DOI：
10.1161/hypertensionaha.109.143404
复制
发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Pao,AlanC
中科院分区：
文献类型：
--
作者：
Rajagopal,Madhumitha;Pao,AlanC
在肾脏中，尿盐排泄调节的缺陷会导致细胞外液体体积膨胀，导致盐敏感型高血压。先前的研究表明，当大鼠保持高氯化钠(NaC L)饮食时，肾髓质中腺苷的产量增加，腺苷受体的表达也发生了平行的变化。这些研究表明，肾脏中的腺苷信号可以对高盐负荷做出反应；然而，这些腺苷信号变化的功能后果尚不清楚。我们用永生化细胞系MIMCD-K2，一种小鼠肾内髓集合管的模型系统，用Ussing小室系统研究了腺苷对氯化钠跨内髓集合管上皮转运的直接影响。当上皮细胞Na+通道被抑制时，在mIMCD-K2细胞膜顶侧加入腺苷以剂量依赖的方式刺激短路电流。这种短路电流的增加可被囊性纤维化跨膜电导调节剂CL−通道抑制剂抑制。一组腺苷受体激动剂和拮抗剂的药理研究表明，腺苷激活顶端A2B腺苷受体以增强短路电流。此外，将腺苷应用于mIMCD-K2细胞膜增加细胞内cAMP，而抑制蛋白激酶A则完全阻断腺苷反应。总之，我们的发现表明，腺苷通过激活顶端A2B受体和cAMP/蛋白激酶A信号通路，通过囊性纤维化跨膜电导调节器刺激MIMCD-K2细胞Cl盐的分泌。我们认为，这一腺苷受体途径可能是在高饮食盐摄入量的情况下增加尿盐排泄的一种机制。
In the kidney, defects in the regulation of urine salt excretion can result in extracellular fluid volume expansion, leading to salt-sensitive hypertension. Previous studies have demonstrated that, when rats are maintained on a high sodium chloride (NaCl) diet, adenosine production increases in the renal medulla with parallel changes in adenosine receptor expression. These studies suggest that adenosine signaling in the kidney can respond to high NaCl loading; however, the functional consequences of these changes in adenosine signaling are not clear. We used the immortalized cell line mIMCD-K2, a murine model system for the renal inner medullary collecting duct, to study the direct effects of adenosine on NaCl transport across the inner medullary collecting duct epithelium with an Ussing chamber system. When epithelial Na+channels were inhibited, the addition of adenosine to the apical side of mIMCD-K2 cell sheets stimulated short-circuit current in a dose-dependent manner. This increase in short-circuit current was inhibited by a cystic fibrosis transmembrane conductance regulator Cl−channel inhibitor. Pharmacological studies with a panel of adenosine receptor agonists and antagonists demonstrated that adenosine activates apical A2b adenosine receptors to enhance the short-circuit current. Furthermore, adenosine application to mIMCD-K2 cell sheets increased intracellular cAMP, whereas inhibition of protein kinase A completely blocked the adenosine response. Together, our findings indicate that adenosine stimulates Cl−secretion through the cystic fibrosis transmembrane conductance regulator in mIMCD-K2 cells by activating apical A2b receptors and signaling through cAMP/protein kinase A. We propose that this adenosine receptor pathway may provide one mechanism for enhancing urine NaCl excretion in the setting of high dietary NaCl intake.