Neonatal Proximal Tubule Acidification

新生儿比成人更容易发生液体和电解质紊乱，部分原因是 未成熟肾脏我们已经表明，有显着的差异之间的速度和 新生大鼠近端小管NaCl和NaHCO 3的转运特征较成人明显。 近端小管对NaCl和NaHCO 3的重吸收在很大程度上依赖于管腔内 Na+/H+交换器，在成人中为NHE 3。新生儿几乎没有顶膜NHE 3 尽管具有显著量的Na+/H+交换剂活性。我们提供的证据表明， 新生儿具有与成人不同的Na+/H+同种型。我们发现， 新生儿近曲小管膜表达丰富的NHE 8和少量的NHE 3， 与主要表达NHE 3和少量NHE 8的成体相比。然而，我们非常了解 关于NHE 8的功能特性，其调节以及引起同种型的原因， 在出生后发育过程中转换为NHE 3。本提案的目的是描述 NHE 8在体外和体内的功能。我们将使用高度敏感的pH选择性技术 全细胞贴片配置上的电极，我们可以完全控制额外的， 细胞内环境来表征NHE 8的功能。我们将研究 负责在出生后发育过程中从NHE 8的亚型转换， 研究肾脏发育的动物模型，肾上腺切除甲状腺功能减退大鼠，其中 近端小管Na+/H+交换和NHE 3的成熟几乎在新生儿期被阻止 水平我们已经表明，NHE 3水平增加的糖皮质激素和甲状腺激素， 激素.肾上腺切除-甲状腺功能减退大鼠将使我们能够测试的假设， 新生儿的相对甲状腺功能减退、糖皮质激素缺乏状态阻止了 NHE 3产生新生儿所需的具有不同调节特性的另一种亚型 近端小管酸化。我们将研究NHE 8是否被相反的方向调节， 糖皮质激素和甲状腺激素导致成人下调。最后，我们现在 我们有一个NHE 8无效的小鼠，这将使我们能够检查这个相对功能的重要性， 发育中NHE亚型在肾酸化中的作用及其在 新生儿和成人的酸中毒。

Neonates are more prone to fluid and electrolyte disorders than adults due, in part, to the immature kidney. We have shown that there are marked differences between the rate and characteristics of neonatal proximal tubule NaCl and NaHCO3 transport than that in the adult. Proximal tubule reabsorption of NaCl and NaHCO3 is dependent in large part on the luminal Na+/H+ exchanger, which in adults is NHE3. Neonates have almost no apical membrane NHE3 despite having a significant amount of Na+/H+ exchanger activity. We provide evidence that the neonate has a different Na+/H+ isoform than the adult. We show that the brush border membrane of the neonatal proximal tubule expresses abundant NHE8 and little NHE3, compared to the adult that primarily expresses NHE3 and little NHE8. However, we know very little about the functional characteristics NHE8, its regulation and what causes the isoform switch during postnatal development to NHE3. The aims of this proposal are to characterize the function of NHE8 in vitro and in vivo. We will use a highly sensitive technique of pH selective electrodes on the whole-cell patch configuration where we have total control of the extra and intracellular milieu to characterize the function of NHE8. We will examine the factors responsible for the isoform switch from NHE8 during postnatal development using a novel animal model to study renal development, the adrenalectomized-hypothyroid rat, where the maturation of proximal tubule Na+/H+ exchange and NHE3 is nearly arrested at the neonatal level. We have shown that NHE3 levels are increased by the glucocorticoids and thyroid hormone. The adrenalectomized-hypothyroid rat will allow us to test the hypothesis that the relative hypothyroid, glucocorticoid deficient state of the neonate prevents the expression of NHE3 making another isoform with different regulatory properties necessary for neonatal proximal tubule acidification. We will examine if NHE8 is regulated in the opposite direction by glucocorticoids and thyroid hormone resulting in down regulation in the adult. Finally, we now have a NHE8 null mouse that will allow us to examine the relative functional importance of this developmental NHE isoform in renal acidification and its relative importance in response to acidosis in both neonates and adults.