Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
J Am Soc Nephrol. 2013 Feb;24(2):218-27. doi: 10.1681/ASN.2012050449. Epub 2012 Dec 20.
Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.
加压素通过腺苷酸环化酶刺激的环 AMP 调节集合管中的钠重吸收，环 AMP 存在多种同工型；参与加压素刺激的钠转运的特定同工型尚不清楚。为了评估这一点，我们研究了在集合管的主细胞中特异性缺乏腺苷酸环化酶 VI 的小鼠。敲除小鼠的尿量增加，尿钠浓度降低，但无论钠摄入量如何，它们的尿钠排泄、动脉压或脉搏率均无明显变化。然而，敲除小鼠的血浆肾素浓度升高，表明存在代偿反应。缬沙坦可显著降低敲除小鼠的动脉压，但对对照小鼠无影响。敲除小鼠的肾脏皮质 mRNA 中所有三种上皮钠通道（ENaC）同工型的含量降低，这些动物的总细胞钠通道同工型α和γ也减少。对分离的皮质集合管进行膜片钳分析显示，钠通道的基础活性没有差异，但敲除小鼠的加压素刺激 ENaC 开放概率和顶端膜通道数量被消除。总之，这些数据表明，腺苷酸环化酶 VI 介导肾脏中加压素刺激的 ENaC 活性。
