Neonatal Proximal Tubule Acidification

描述（由申请人提供）：新生儿和成人肾脏之间存在临床重要差异。与成人相比，新生儿肾脏的肾小球滤过率较低，肾小管不成熟。肾小管不成熟使新生儿易发生液体和电解质紊乱。成人近端小管重吸收80%的过滤的碳酸氢盐和60%的过滤的NaCl。 在成熟的近曲小管中，大多数近曲小管酸化是由于顶端Na+/H+交换器（NHE 3）。Na+/H+交换器与Cl-/碱交换器并联也介导跨细胞NaCl运输。NaCl在成熟体节中的运输有一半是被动的、沿细胞运输的。新生儿近端小管几乎检测不到NHE 3水平。这项建议将研究是什么产生的NHE 3和近端小管NaCl运输的发展增加。在大鼠生命的前三周，皮质酮水平增加100倍，甲状腺激素水平增加10倍。我们最近已经证明，糖皮质激素的这种增加介导了大部分，但不是全部，NHE 3的增加。第一个目标将检查糖皮质激素增加NHE 3的机制。第二个目标将检查是否在一种新的动物模型中完全阻止NHE 3的成熟，即甲状腺功能减退糖皮质激素缺乏的新生大鼠。除了主动运输的发育变化，我们最近已经证明，有显着差异的细胞旁途径在未成熟的小管，影响NaCl运输的被动组件。而一半的NaCl运输是旁细胞在成人近端小管，基本上没有被动的NaCl运输在新生儿段。第三个目标将表征新生儿和成人近端小管旁细胞通路的生理和分子特征，以确定为什么新生儿近端小管中没有被动NaCl转运。

DESCRIPTION (provided by applicant): There are clinically important differences between the neonatal and adult kidney. The neonatal kidney has a lower glomerular filtration rate and immature tubules compared to the adult. Tubular immaturity predisposes neonates to develop fluid and electrolyte disorders. The adult proximal tubule reabsorbs 80 percent of the filtered bicarbonate and 60 percent of the filtered NaCl. Most of proximal tubule acidification in the mature proximal tubule is due to the apical Na+/H+ exchanger (NHE3). The Na+/H+ exchanger in parallel with a Cl-/base exchanger also mediates transcellular NaCl transport. Half of NaCl transport in the mature segment is passive and paracellular. Neonatal proximal tubules have almost an undetectable level of NHE3. This proposal will examine what produces the developmental increase in NHE3 and in proximal tubule NaCl transport. There is a 100-fold increase in corticosterone level and a 10-fold increase in thyroid hormone level during the first three weeks of life in the rat. We have recently demonstrated that this rise in glucocorticoids mediates most, but not all, of the increase in NHE3. The first aim will examine the mechanisms whereby glucocorticoids increase NHE3. The second aim will examine if the maturation of NHE3 is totally prevented in a novel animal model, a hypothyroid glucocorticoid deficient neonatal rat. In addition to the developmental changes in active transport, we have recently demonstrated that there are significant differences in the paracellular pathway in immature tubules, which impact the passive component of NaCl transport. Whereas one half of NaCl transport is paracellular in the adult proximal tubule, there is essentially no passive NaCl transport in the neonatal segment. The third aim will characterize the physiologic and molecular characteristics of the neonatal and adult proximal tubule paracellular pathway to determine why there is no passive NaCl transport in the neonatal proximal tubule.