Abstract：
Hyponatremia is the most common disorder of electrolyte imbalances. It is necessary to develop new type of diuretics to treat hyponatremia without losing electrolytes. Urea transporters (UT) play an important role in the urine concentrating process and have been proved as a novel diuretic target. In this study, rat and mouse syndromes of inappropriate antidiuretic hormone secretion (SIADH) models were constructed and analyzed to determine if UTs are a promising drug target for treating hyponatremia. Experimental results showed that 100 mg/kg UT inhibitor 25a significantly increased serum osmolality (from 249.83 ± 5.95 to 294.33 ± 3.90 mOsm/kg) and serum sodium (from 114 ± 2.07 to 136.67 ± 3.82 mmol/L) respectively in hyponatremia rats by diuresis. Serum chemical examination showed that 25a neither caused another electrolyte imbalance nor influenced the lipid metabolism. Using UT-A1 and UT-B knockout mouse SIADH model, it was found that serum osmolality and serum sodium were lowered much less in UT-A1 knockout mice than in UT-B knockout mice, which suggest UT-A1 is a better therapeutic target than UT-B to treat hyponatremia. This study provides a proof of concept that UT-A1 is a diuretic target for SIADH-induced hyponatremia and UT-A1 inhibitors might be developed into new diuretics to treat hyponatremia.
摘要：
低钠血症是最常见的电解质失衡障碍。有必要开发新型利尿剂来治疗低钠血症而不损失电解质。尿素转运蛋白（UT）在尿液浓缩过程中起着重要作用，已被证明是一种新型的利尿剂靶标。在这项研究中,我们构建并分析了抗利尿激素分泌异常综合征(SIADH)大鼠和小鼠模型,以确定UTs是否是治疗低钠血症的有希望的药物靶点.实验结果表明，100mg/kgUT抑制剂25a可显著增加低钠血症大鼠的血清渗透压浓度（从249.83±5.95到294.33±3.90mOsm/kg）和血清钠（从114±2.07到136.67±3.82mmol/L）。血清化学检查显示25a既没有引起另一种电解质失衡，也没有影响脂质代谢。使用UT-A1和UT-B敲除小鼠SIADH模型,发现UT-A1敲除小鼠的血清渗透压和血清钠的降低比UT-B敲除小鼠的低得多，这表明UT-A1是比UT-B更好的治疗低钠血症的治疗靶点。这项研究证明了UT-A1是SIADH诱导的低钠血症的利尿剂靶标，UT-A1抑制剂可能会发展成为治疗低钠血症的新利尿剂。
