Regulation of cell survival by Na+/H+ exchanger-1.
Regulation of cell survival by Na+/H+ exchanger-1.
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DOI：
10.1152/ajprenal.90212.2008
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发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
J. Schelling;B. G. Abu Jawdeh
中科院分区：
文献类型：
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作者：
J. Schelling;B. G. Abu Jawdeh
Na(+)/H(+)交换器-1(NHE1)是一种普遍存在的质膜Na(+)/H(+)交换器，通常与维持细胞内容量和pH有关。在体外培养的肾小管上皮细胞中，除了NHE1在Na(+)/H(+)电子中和转运中的作用外，NHE1胞浆尾段作为支架，通过与Ezrin/Radioxin/Moesin(ERM)蛋白和磷脂酰肌醇4，5-二磷酸结合，启动一个信号复合体的形成，最终导致Akt激活和对抗最初的凋亡应激。在强烈的细胞凋亡刺激下，肾小管上皮细胞NHE1是半胱氨酸天冬氨酸氨基转移酶底物，蛋白水解酶的裂解可能导致细胞死亡。在体内，在链脲佐菌素诱导的糖尿病、输尿管梗阻和阿霉素诱导的足细胞毒性后，NHE1的遗传或药理学功能丧失会导致肾小管上皮细胞凋亡和肾功能障碍。综上所述，大量的体内和体外数据表明，NHE1调节肾小管上皮细胞的存活。与NHE1作为一种不重要的“家务”蛋白的内涵不同，这篇综述强调了NHE1的活性对于对抗肾小管萎缩和慢性肾脏疾病进展至关重要。
Na(+)/H(+) exchanger-1 (NHE1) is a ubiquitous plasma membrane Na(+)/H(+) exchanger typically associated with maintenance of intracellular volume and pH. In addition to the NHE1 role in electroneutral Na(+)/H(+) transport, in renal tubular epithelial cells in vitro the polybasic, juxtamembrane NHE1 cytosolic tail domain acts as a scaffold, by binding with ezrin/radixin/moesin (ERM) proteins and phosphatidylinositol 4,5-bisphosphate, which initiates formation of a signaling complex that culminates in Akt activation and opposition to initial apoptotic stress. With robust apoptotic stimuli renal tubular epithelial cell NHE1 is a caspase substrate, and proteolytic cleavage may permit progression to apoptotic cell death. In vivo, genetic or pharmacological NHE1 loss of function causes renal tubule epithelial cell apoptosis and renal dysfunction following streptozotocin-induced diabetes, ureteral obstruction, and adriamycin-induced podocyte toxicity. Taken together, substantial in vivo and in vitro data demonstrate that NHE1 regulates tubular epithelial cell survival. In contrast to connotations of NHE1 as an unimportant "housekeeping" protein, this review highlights that NHE1 activity is critical for countering tubular atrophy and chronic renal disease progression.