Shi Yimin, Li Chunling, Thomsen Klaus, Jørgensen Troels Munch, Knepper Mark A, Nielsen Søren, Djurhuus Jens Christian, Frøkiaer Jørgen
Institute of Experimental Clinical Research, Aarhus University, Aarhus, Denmark.
Kidney Int. 2004 Jul;66(1):203-15. doi: 10.1111/j.1523-1755.2004.00721.x.
Congenital urinary tract obstruction is a common cause of renal insufficiency in the neonate and during infancy. Recently, we demonstrated that ureteral obstruction in adult rats is associated with reduction in the abundance of renal aquaporins (AQPs) and renal sodium transporters, which paralleled an impaired urinary concentrating capacity.
In the present study, renal handling of sodium and water, together with the expression of renal aquaporins and major renal sodium transporters, was examined in rats with neonatally induced partial unilateral ureteral obstruction (PUUO) within the first 48 hours of life to clarify the molecular mechanisms involved in the tubular functional defects in response to congenital obstruction. Rats were then followed for 12 or 24 weeks.
Neonatal PUUO caused a progressive reduction in single kidney glomerular filtration rate (SKGFR) on the obstructed side to 43% of controls at 12 weeks (115 +/- 28 vs. 267 +/- 36 microL/min/100g bw, P < 0.05), and 31% of controls at 24 weeks (106 +/- 24 vs. 343 +/- 41 microL/min/100g bw, P < 0.05). Na-K-ATPase abundance was decreased in the obstructed kidney compared with the nonobstructed kidney at 24 weeks (79 +/- 6%, P < 0.05), and the abundance of bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) located to the medullary thick ascending limb (mTAL) of the obstructed kidney was significantly reduced both at 12 weeks (42 +/- 10%, P < 0.05) and 24 weeks (50 +/- 10%, P < 0.05). Immunohistochemistry confirmed down-regulation of BSC-1 both at 12 and 24 weeks after onset of obstruction. Consistent with this, sodium excretion from the obstructed kidney was increased at 12 weeks (0.13 +/- 0.03 vs. 0.04 +/- 0.01 micromol/min/100g bw, P < 0.05), and persisted 24 weeks after onset of PUUO (0.15 +/- 0.02 vs. 0.06 +/- 0.01 micromol/min/100g bw, P < 0.05). AQP2 abundance in the collecting duct was also reduced both at 12 weeks (68 +/- 5%, P < 0.05) and at 24 weeks (69 +/- 13%, P < 0.05). Consistent with this, solute-free water reabsorption was decreased in the obstructed kidney at 12 weeks (0.61 +/- 0.42 vs. 1.97 +/- 0.63 microL/min/100g bw, P < 0.05) and remained decreased after 24 weeks of PUUO (0.42 +/- 0.04 vs. 1.56 +/- 0.39 microL/min/100g bw, P < 0.05).
Major sodium transporters and aquaporins in the obstructed kidney are down-regulated in response to neonatally induced PUUO, which indicates that these transporters may play a crucial role for the persistent reduction in renal handling of sodium and water in response to PUUO.
先天性尿路梗阻是新生儿及婴儿期肾功能不全的常见原因。最近，我们发现成年大鼠输尿管梗阻与肾水通道蛋白（AQP）及肾钠转运体丰度降低有关，这与尿浓缩能力受损平行。
在本研究中，对出生后48小时内诱导产生新生儿期部分单侧输尿管梗阻（PUUO）的大鼠进行肾钠和水的处理，以及肾水通道蛋白和主要肾钠转运体表达的检测，以阐明先天性梗阻后肾小管功能缺陷所涉及的分子机制。然后对大鼠进行12周或24周的随访。
新生儿期PUUO使梗阻侧单肾肾小球滤过率（SKGFR）逐渐降低，在12周时降至对照组的43%（115±28 vs. 267±36微升/分钟/100克体重，P<0.05），24周时降至对照组的31%（106±24 vs. 343±41微升/分钟/100克体重，P<0.05）。与未梗阻肾相比，24周时梗阻肾中Na-K-ATP酶丰度降低（79±6%，P<0.05），位于梗阻肾髓袢升支粗段（mTAL）的布美他尼敏感的Na-K-2Cl协同转运体（BSC-1）丰度在12周（42±10%，P<0.05）和24周（50±10%，P<0.05）时均显著降低。免疫组化证实梗阻后12周和24周时BSC-1均下调。与此一致，梗阻肾的钠排泄在12周时增加（0.13±0.03 vs. 0.04±0.01微摩尔/分钟/100克体重，P<0.05），且在PUUO发生24周后仍持续增加（0.15±0.02 vs. 0.06±0.01微摩尔/分钟/100克体重，P<0.05）。集合管中AQP2丰度在12周（68±5%，P<0.05）和24周（69±13%，P<0.05）时也均降低。与此一致，梗阻肾在12周时无溶质水重吸收减少（0.61±0.42 vs. 1.97±0.63微升/分钟/100克体重，P<0.05），且在PUUO 24周后仍保持降低（0.42±0.0．4 vs. 1.56±0.39微升/分钟/100克体重，P<0.05）。
梗阻肾中的主要钠转运体和水通道蛋白因新生儿期诱导的PUUO而下调，这表明这些转运体可能在PUUO后肾对钠和水的处理持续减少中起关键作用。
