PDF(Sci-hub)
Abstract：
We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.
摘要：
我们已经确定了一个创始人纯合E3_E4del：在AGT基因中编码血管紧张素原的2870bp缺失9bp插入，该基因负责常染色体隐性遗传性肾小管发育不全（ARRTD），具有几乎致命的结果。大剂量氢化可的松治疗成功挽救了一名血清血管紧张素原（AGT）升高的患者，AngI,和AngII水平。通过体外功能研究检查了由这种AGT突变引起的ARRTD的发病机理和氢化可的松的潜在治疗作用。这种截短的AGT蛋白的表达相对较低，具有剂量依赖性。这种截短的突变减少了突变AGT和肾素之间的相互作用。截短的AGT也改变了糖皮质激素受体（GR）依赖性的反式激活，表明AGT可能通过改变糖皮质激素依赖性反式激活来影响近曲小管的发育。在肝细胞中，氢化可的松通过增强突变AGT的稳定性并增加其与肾素的结合来增加AGT水平。因此,在携带该AGT突变的患者中,氢化可的松可通过增强的稳定性和与截短的AGT的肾素的相互作用发挥治疗作用。
