cAMP inhibition of murine intestinal Na+/H+ exchange requires CFTR-mediated cell shrinkage of villus epithelium
cAMP inhibition of murine intestinal Na+/H+ exchange requires CFTR-mediated cell shrinkage of villus epithelium
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DOI：
10.1016/s0016-5085(03)01212-5
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发表时间：
2003-10-01
期刊：
影响因子：
29.4
通讯作者：
Clarke, LL
中科院分区：
文献类型：
--
作者：
Gawenis, LR;Franklin, CL;Clarke, LL
背景和目标：与正常受试者的肠道不同，囊性纤维化患者和囊性纤维化跨膜传导调节蛋白缺失（CFTR-）小鼠的小肠上皮细胞对细胞内环磷酸腺苷的刺激不产生反应，抑制电中性NaCl吸收。由于CFTR介导的阴离子分泌与隐窝细胞体积的变化有关，我们假设CFTR介导的绒毛上皮细胞体积减少是近端小肠细胞内环磷酸腺苷抑制Na+/H+交换器（主要是Na+/H+交换器3）活性所必需的。方法. CFTR+、CFTR-、基底外侧膜Na+/K+/2Cl（-）共转运蛋白NKCC 1（+）和NKCC 1（-）小鼠空肠跨上皮Na-22通量与中绒毛区上皮细胞体积的变化相关。结果如下：细胞内环磷酸腺苷的刺激导致CFTR+空肠中Na+/H+交换介导的Na+吸收（J（ms）（NHE））的停止，但对CFTR-空肠中的J（ms）（NHE）没有影响。细胞体积指数表明CFTR+空肠中绒毛上皮细胞的体积减少约30%，但在细胞内环磷酸腺苷刺激后CFTR-上皮细胞没有变化。相反，高渗培养基诱导的细胞收缩抑制CFTR+和CFTR-小鼠中的J（ms）（NHE）。布美他尼通过阻断刺激的CFTR+空肠的Na+/K+/2Cl（-）协同转运蛋白NKCC 1来抑制Cl-分泌，从而阻止了绒毛上皮的最大体积减少，并恢复了约40%的J（ms）（NHE）MS。同样，在NKCC 1（-）空肠中，J（ms）（NHE）和细胞体积不受细胞内环磷酸腺苷刺激的影响。结论：这些研究结果表明，以前未认识到的作用，功能CFTR绒毛上皮细胞表达：调节Na+/H+交换3介导的Na+吸收上皮细胞体积的改变。
Background & Aims: Unlike the intestine of normal subjects, small-intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein-null (CFTR-) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption. Because CFTR-mediated anion secretion has been associated with changes in crypt cell volume, we hypothesized that CFTR-mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na+/H+ exchanger (primarily Na+/H+ exchanger 3) activity in the proximal small intestine. Methods. Transepithelial Na-22 flux across the jejuna of CFTR+, CFTR-, the basolateral membrane Na+/K+/2Cl(-) co-transporter protein NKCC1(+), and NKCC1(-) mice were correlated with changes in epithelial cell volume of the midvillus region. Results: Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na+/H+ exchanger-mediated Na+ absorption (J(ms)(NHE)) in CFTR+ jejunum but had no effect on J(ms)(NHE) across CFTR- jejunum. Cell volume indices indicated an approximately 30% volume reduction of villus epithelial cells in CFTR+ jejunum but no changes in CFTR- epithelium after intracellular cyclic adenosine monophosphate stimulation. In contrast, cell shrinkage induced by hypertonic medium inhibited J(ms)(NHE) in both CFTR+ and CFTR- mice. Bumetanide treatment to inhibit Cl- secretion by blockade of the Na+/K+/2Cl(-) co-transporter, NKCC1, of stimulated CFTR+ jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40% of J(ms)(NHE) MS. Likewise, J(ms)(NHE) and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in NKCC1(-) jejuna. Conclusions: These findings show a previously unrecognized role of functional CFTR expressed in villus epithelium: regulation of Na+/H+ exchanger 3-mediated Na+ absorption by alteration of epithelial cell volume.