Emory University, Department of Medicine, Renal Division, Atlanta, Georgia, USA.
NephroDI Therapeutics, Philadelphia, Pennsylvania, USA.
JCI Insight. 2021 Apr 22;6(8):146419. doi: 10.1172/jci.insight.146419.
Nephrogenic diabetes insipidus (NDI) patients produce large amounts of dilute urine. NDI can be congenital, resulting from mutations in the type-2 vasopressin receptor (V2R), or acquired, resulting from medications such as lithium. There are no effective treatment options for NDI. Activation of PKA is disrupted in both congenital and acquired NDI, resulting in decreased aquaporin-2 phosphorylation and water reabsorption. We show that adenosine monophosphate-activated protein kinase (AMPK) also phosphorylates aquaporin-2. We identified an activator of AMPK, NDI-5033, and we tested its ability to increase urine concentration in animal models of NDI. NDI-5033 increased AMPK phosphorylation by 2.5-fold, confirming activation. It increased urine osmolality in tolvaptan-treated NDI rats by 30%-50% and in V2R-KO mice by 50%. Metformin, another AMPK activator, can cause hypoglycemia, which makes it a risky option for treating NDI patients, especially children. Rats with NDI receiving NDI-5033 showed no hypoglycemia in a calorie-restricted, exercise protocol. Congenital NDI therapy needs to be effective long-term. We administered NDI-5033 for 3 weeks and saw no reduction in efficacy. We conclude that NDI-5033 can improve urine concentration in animals with NDI and holds promise as a potential therapy for patients with congenital NDI due to V2R mutations.
肾源性尿崩症（NDI）患者会产生大量稀释的尿液。NDI 可分为先天性和获得性，前者由 II 型血管加压素受体（V2R）突变引起，后者由锂等药物引起。目前尚无有效的 NDI 治疗方法。先天性和获得性 NDI 中 PKA 的激活均受到破坏，导致水通道蛋白-2 的磷酸化和水重吸收减少。我们发现环腺苷酸激活的蛋白激酶（AMPK）也能使水通道蛋白-2磷酸化。我们鉴定了一种 AMPK 激活剂 NDI-5033，并测试了其在 NDI 动物模型中增加尿液浓缩的能力。NDI-5033 使 AMPK 的磷酸化增加了 2.5 倍，证实了其激活作用。它使托伐普坦治疗的 NDI 大鼠和 V2R-KO 小鼠的尿液渗透压增加了 30%-50%和 50%。另一种 AMPK 激活剂二甲双胍会导致低血糖，这使其成为治疗 NDI 患者（尤其是儿童）的一种危险选择。在热量限制和运动方案中，接受 NDI-5033 治疗的 NDI 大鼠没有出现低血糖。先天性 NDI 的治疗需要长期有效。我们给予 NDI-5033 治疗 3 周，未发现疗效降低。我们的结论是，NDI-5033 可以改善 NDI 动物的尿液浓缩，并有望成为 V2R 突变导致的先天性 NDI 患者的潜在治疗方法。
