Schulz Angela, Römpler Holger, Mitschke Doreen, Thor Doreen, Schliebe Nicole, Hermsdorf Thomas, Strotmann Rainer, Sangkuhl Katrin, Schöneberg Torsten
a University of Leipzig, Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Johannisallee 30, 04103, Leipzig, Germany.
b University of Leipzig, Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Johannisallee 30, 04103, Leipzig, Germany.
Expert Rev Endocrinol Metab. 2006 Nov;1(6):727-741. doi: 10.1586/17446651.1.6.727.
Maintenance of water and electrolyte homeostasis is central to mammalian survival and, therefore, under stringent hormonal control. Water homeostasis is achieved by balancing fluid intake with water excretion, governed by the antidiuretic action of arginine vasopressin. Arginine vasopressin stimulation of renal V vasopressin receptors in the basolateral membrane of principal cells induces aquaporin-2-mediated water reabsorption in the kidney. The importance of this system is apparent when mutations inactivate V vasopressin receptors and aquaporin-2 and cause the clinical phenotype of nephrogenic diabetes insipidus. To date, over 190 mutations in the V vasopressin receptors gene (AVPR2) and approximately 38 mutations in the aquaporin-2 gene have been identified in patients with inherited nephrogenic diabetes insipidus. Extensive in vitro expression and mutagenesis studies of V vasopressin receptors and aquaporin-2 have provided detailed insights into the molecular mechanisms of G-protein-coupled receptor and water channel dysfunction per se. Targeted deletions of AVPR2 and AQP2 in mice have extended the knowledge of nephrogenic diabetes insipidus pathophysiology and have stimulated testing of old and new ideas to therapeutically restore normal kidney function in animal models and patients with this disease. In this review, we summarize the current knowledge relevant to understand the molecular basis of inherited nephrogenic diabetes insipidus forms and the rationales for the current pharmacological treatment of patients with this illness.
维持水和电解质平衡对于哺乳动物的生存至关重要，因此受到严格的激素控制。水的平衡是通过使液体摄入量与水排泄量相平衡来实现的，这由精氨酸加压素的抗利尿作用所调控。精氨酸加压素刺激主细胞基底外侧膜上的肾V加压素受体，可诱导肾脏中 aquaporin-2 介导的水重吸收。当该系统中的突变使V加压素受体和 aquaporin-2 失活并导致肾性尿崩症的临床表型时，这一系统的重要性就显而易见了。迄今为止，在遗传性肾性尿崩症患者中已鉴定出超过190种V加压素受体基因（AVPR2）突变和约38种aquaporin-2基因的突变。对V加压素受体和aquaporin-2进行的广泛体外表达和诱变研究，为G蛋白偶联受体和水通道功能障碍本身的分子机制提供了详细的见解。在小鼠中对AVPR2和AQP2进行靶向缺失，扩展了对肾性尿崩症病理生理学的认识，并激发了对新旧理念的测试，以在动物模型和患有这种疾病的患者中治疗性地恢复正常肾功能。在本综述中，我们总结了当前与理解遗传性肾性尿崩症形式的分子基础以及对该疾病患者当前药物治疗原理相关的知识。
