Neonatal Proximal Tubule Acidification

描述(由申请人提供)：新生儿肾脏与成人肾脏在临床上有重要区别。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。肾小管不成熟易使新生儿发生液体和电解质紊乱。成人近端小管重新吸收80%过滤后的碳酸氢盐和60%过滤后的氯化钠。近端小管的酸化主要是由心尖Na/H交换器(NHE3)引起的。Na/H交换器与Cl-/碱交换器并行，也介导了跨细胞的氯化钠转运。盐在成熟段的运输有一半是被动的和旁细胞的。新生儿近端小管的NHE3水平几乎检测不到。这项建议将研究是什么导致NHE3和近端小管氯化钠转运的发育增加。在大鼠出生的前三周，皮质酮水平增加了100倍，甲状腺激素水平增加了10倍。我们最近证明，糖皮质激素的增加是NHE3增加的主要原因，但不是全部。第一个目标是研究糖皮质激素增加NHE3的机制。第二个目的是检验在一种新的动物模型--甲状腺激素缺乏的新生大鼠中，NHE3的成熟是否完全被阻止。除了主动转运的发育变化外，我们最近还发现，在未成熟的小管中，细胞旁途径存在显著差异，这影响了盐运输的被动成分。在成人近端小管中有一半的氯化钠转运是近端细胞的，而在新生儿段基本上没有被动的氯化钠转运。第三个目标将描述新生儿和成人近端小管细胞旁通路的生理和分子特征，以确定为什么新生儿近端小管没有被动的氯化钠转运。

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.