Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.
Am J Physiol Regul Integr Comp Physiol. 2010 Nov;299(5):R1360-8. doi: 10.1152/ajpregu.00007.2010. Epub 2010 Aug 18.
The serum bicarbonate in neonates is lower than adults due in large part to a lower rate of proximal tubule acidification. It is unclear if the neonatal proximal tubule is functioning at maximal capacity or if the proximal tubule can respond to metabolic acidosis as has been described in adult proximal tubules. We find that neonatal mouse brush-border membranes have a lower Na(+)/H(+) exchanger (NHE) 3 protein abundance (neonate 0.11 ± 0.05 vs. adult 0.64 ± 0.07; P < 0.05) and a higher NHE8 protein abundance (neonate 1.0 ± 0.01 vs. adult 0.13 ± 0.09; P < 0.001) compared with adults. To examine if neonates can adapt to acidosis, neonatal mice were gavaged with either acid or vehicle for 4 days, resulting in a drop in serum bicarbonate from 19.5 ± 1.0 to 8.9 ± 0.6 meq/l (P < 0.001). Proximal convoluted tubule Na(+)/H(+) exchanger activity (dpH(i)/dt) was 1.68 ± 0.19 pH units/min in control tubules and 2.49 ± 0.60 pH units/min in acidemic neonatal mice (P < 0.05), indicating that the neonatal proximal tubule can respond to metabolic acidosis with an increase in Na(+)/H(+) exchanger activity. Similarly, brush-border membrane vesicles from neonatal rats had an increase in Na(+)/H(+) exchanger activity with acidemia that was almost totally inhibited by 10(-6) M 5-(N-ethyl-n-isopropyl)-amiloride, a dose that has little effect on NHE3 but inhibits NHE8. There was a significant increase in both NHE3 (vehicle 0.35 ± 0.07 vs. acid 0.73 ± 0.07; P < 0.003) and NHE8 brush-border membrane protein abundance (vehicle 0.41 ± 0.05 vs. acid 0.73 ± 0.06; P < 0.001) in acidemic mouse neonates compared with controls. A comparable increase in NHE3 and NHE8 was found in neonatal rats with acidosis. In conclusion, the neonatal proximal tubule can adapt to metabolic acidosis with an increase in Na(+)/H(+) exchanger activity.
新生儿的血清碳酸氢盐水平低于成人，这在很大程度上是由于近端肾小管酸化率较低。目前尚不清楚新生儿的近端小管是否处于最大功能状态，或者近端小管是否能够像成人的近端小管那样对代谢性酸中毒做出反应。我们发现，与成人相比，新生小鼠的刷状缘膜上的钠氢交换蛋白 3（NHE3）蛋白丰度较低（新生儿 0.11 ± 0.05 对成人 0.64 ± 0.07；P < 0.05），而 NHE8 蛋白丰度较高（新生儿 1.0 ± 0.01 对成人 0.13 ± 0.09；P < 0.001）。为了研究新生儿是否可以适应酸中毒，我们用酸或载体灌胃新生小鼠 4 天，导致血清碳酸氢盐从 19.5 ± 1.0 降至 8.9 ± 0.6 meq/l（P < 0.001）。在对照组中，近端卷曲小管的钠氢交换器活性（dpH(i)/dt）为 1.68 ± 0.19 pH 单位/分钟，而在酸中毒的新生小鼠中为 2.49 ± 0.60 pH 单位/分钟（P < 0.05），这表明新生儿近端小管可以通过增加钠氢交换器活性来应对代谢性酸中毒。同样，来自新生大鼠的刷状缘膜囊泡在酸中毒时钠氢交换器活性增加，而 10(-6) M 5-（N-乙基-N-异丙基）-阿米洛利几乎完全抑制了这种增加，这种剂量对 NHE3 影响很小，但抑制了 NHE8。与对照组相比，酸中毒的新生小鼠的 NHE3（载体 0.35 ± 0.07 对酸 0.73 ± 0.07；P < 0.003）和 NHE8 刷状缘膜蛋白丰度（载体 0.41 ± 0.05 对酸 0.73 ± 0.06；P < 0.001）均显著增加。在酸中毒的新生大鼠中也发现了 NHE3 和 NHE8 的类似增加。总之，新生儿近端小管可以通过增加钠氢交换器活性来适应代谢性酸中毒。
