Fernández-Llama P, Andrews P, Ecelbarger C A, Nielsen S, Knepper M
Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, Maryland, USA.
Kidney Int. 1998 Jul;54(1):170-9. doi: 10.1046/j.1523-1755.1998.00984.x.
Several pathophysiological states associated with deranged water balance are associated with altered expression and/or intracellular distribution of aquaporin water channels. The possible role of dysregulation of thick ascending limb NaCl transporters, which are responsible for countercurrent multiplication in the kidney, has not been evaluated.
Semiquantitative immunoblotting and immunocytochemistry were carried out in the kidneys of rat with adriamycin-induced nephrotic syndrome and in vehicle-injected control rats.
Preliminary studies confirmed the presence of a severe concentrating defect. Semiquantitative immunoblotting of outer medullary homogenates demonstrated a marked decrease in the abundance of three thick ascending limb Na+ transporters in nephrotic rats, namely the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), the type 3 Na/H exchanger (NHE-3), and the alpha 1-subunit of the Na-K-ATPase. These results are predictive of a decrease in the NaCl transport capacity of the medullary thick ascending limb and therefore a decrease in countercurrent multiplication. Immunocytochemistry of outer medullary thin sections demonstrated broad (but highly variable) suppression of BSC-1 expression in the outer medullas of adriamycin-nephrotic rats. There was also a large decrease in outer medullary expression of two collecting duct water channels (aquaporin-2 and -3) and the major water channel of the thin descending limb of Henle's loop (aquaporin-1).
The concentrating defect in adriamycin-induced nephrotic syndrome in rats is a consequence of multiple defects in water and solute transporter expression, which would alter both the generation of medullary interstitial hypertonicity and osmotic equilibration in the collecting duct. Whether a similar widespread defect in transporter expression is present in idiopathic nephrotic syndrome is, at this point, untested.
几种与水代谢紊乱相关的病理生理状态与水通道蛋白水通道的表达改变和/或细胞内分布改变有关。负责肾脏逆流倍增的髓袢升支粗段氯化钠转运体失调的可能作用尚未得到评估。
对阿霉素诱导的肾病综合征大鼠及注射溶媒的对照大鼠的肾脏进行半定量免疫印迹和免疫细胞化学检测。
初步研究证实存在严重的浓缩功能缺陷。对肾外髓匀浆进行半定量免疫印迹显示，肾病大鼠髓袢升支粗段的三种钠转运体丰度显著降低，即布美他尼敏感的钠-钾-2氯共转运体（BSC-1）、3型钠/氢交换体（NHE-3）和钠-钾-ATP酶的α1亚基。这些结果预示着髓袢升支粗段的氯化钠转运能力下降，从而逆流倍增能力降低。肾外髓薄片的免疫细胞化学显示，阿霉素肾病大鼠肾外髓中BSC-1的表达受到广泛（但高度可变）抑制。集合管的两种水通道蛋白（水通道蛋白-2和-3）以及亨利袢降支细段的主要水通道蛋白（水通道蛋白-1）在肾外髓的表达也大幅下降。
大鼠阿霉素诱导的肾病综合征中的浓缩功能缺陷是水和溶质转运体表达多重缺陷的结果，这将改变髓质间质高渗的产生以及集合管中的渗透平衡。目前尚不清楚特发性肾病综合征是否存在类似的广泛转运体表达缺陷。
