Wang Yanhua, LaRocque Lauren M, Ruiz Joseph A, Rodriguez Eva L, Sands Jeff M, Klein Janet D
Renal Division, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Biomedicines. 2023 Jun 27;11(7):1844. doi: 10.3390/biomedicines11071844.
Hyponatremia (hypo-osmolality) is a disorder of water homeostasis due to abnormal renal diluting capacity. The body limits the degree to which serum sodium concentration falls through a mechanism called "vasopressin escape". Vasopressin escape is a process that prevents the continuous decrease in serum sodium concentration even under conditions of sustained high plasma vasopressin levels. Previous reports suggest that aldosterone may be involved in the vasopressin escape mechanism. The abilities of aldosterone synthase (Cyp11b2) knockout and wild-type mice to escape from vasopressin were compared. Wild-type mice escaped while the aldosterone synthase knockout mice did not. Both the water channel aquaporin 2 (AQP2) and the urea transporter UT-A1 protein abundances were higher in aldosterone synthase knockout than in wild-type mice at the end of the escape period. Vasopressin escape was also blunted in rats given spironolactone, a mineralocorticoid receptor blocker. Next, the role of the phosphatase, calcineurin (protein phosphatase 2B, PP2B), in vasopressin escape was studied since aldosterone activates calcineurin in rat cortical collecting ducts. Tacrolimus, a calcineurin inhibitor, blunted vasopressin escape in rats compared with the control rats, increased UT-A1, AQP2, and pS256-AQP2, and decreased pS261-AQP2 protein abundances. Our results indicate that aldosterone regulates vasopressin escape through calcineurin-mediated protein changes in UT-A1 and AQP2.
低钠血症（低渗）是一种由于肾脏稀释能力异常导致的水稳态紊乱。机体通过一种称为“血管加压素逃逸”的机制来限制血清钠浓度下降的程度。血管加压素逃逸是一个即使在血浆血管加压素持续高水平的情况下也能防止血清钠浓度持续降低的过程。先前的报道表明醛固酮可能参与血管加压素逃逸机制。比较了醛固酮合酶（Cyp11b2）基因敲除小鼠和野生型小鼠从血管加压素中逃逸的能力。野生型小鼠能够逃逸，而醛固酮合酶基因敲除小鼠则不能。在逃逸期结束时，醛固酮合酶基因敲除小鼠的水通道水通道蛋白2（AQP2）和尿素转运蛋白UT-A1的蛋白丰度均高于野生型小鼠。给予盐皮质激素受体阻滞剂螺内酯的大鼠的血管加压素逃逸也受到抑制。接下来，研究了磷酸酶钙调神经磷酸酶（蛋白磷酸酶2B，PP2B）在血管加压素逃逸中的作用，因为醛固酮可激活大鼠皮质集合管中的钙调神经磷酸酶。与对照大鼠相比，钙调神经磷酸酶抑制剂他克莫司使大鼠的血管加压素逃逸受到抑制，增加了UT-A1、AQP2和pS256-AQP2，并降低了pS261-AQP2的蛋白丰度。我们的结果表明，醛固酮通过钙调神经磷酸酶介导的UT-A1和AQP2蛋白变化来调节血管加压素逃逸。
