Uncompensated polyuria in a mouse model of Bartter's syndrome
Uncompensated polyuria in a mouse model of Bartter's syndrome
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DOI：
10.1073/pnas.090091297
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发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Smithies, O
中科院分区：
文献类型：
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作者：
Takahashi, N;Chernavvsky, DR;Smithies, O
我们用同源重组的方法破坏了小鼠在厚升肢和黄斑致密肾上皮细胞中表达的NaK2Cl共转运体（NKCC2）的基因编码。该基因是几种突变导致人类巴特氏综合征的基因之一，这种综合征的特征是严重的多尿和电解质失衡。纯合子NKCC2-/-幼崽的出生数量与预期相符，外观正常。然而，在第1天，他们表现出细胞外体积减少的迹象（血细胞比容51%；野生型37%）。后来，它们没能茁壮成长。到第7天，它们体积小且明显脱水，表现为肾功能不全、高血浆钾、代谢性酸中毒、不同程度的肾积水和血浆肾素浓度高。没有一只存活到断奶。从第1天开始用吲哚美辛治疗-/-幼崽可以防止生长迟缓，治疗3周后10%的幼崽存活，尽管成年后它们表现出严重的多尿（10毫升/天）、严重的肾积水、低血浆钾、高宽pH值、高钙尿和蛋白尿。用呋塞米（一种NaK2Cl共转运体抑制剂）治疗的野生型小鼠，除了肾积水较轻微外，其表型与吲哚美辛拯救的成年小鼠相似。多尿、高钙尿和蛋白尿的-/-成年小鼠和呋塞米处理野生型小鼠对肾素血管紧张素系统抑制剂、加压素和吲哚美辛无反应。因此，小鼠缺乏NKCC2导致多尿，而在肾元的其他部位没有得到补偿。NKCC2突变动物对于揭示肾脏水和电解质恢复中遗传紊乱的新病理生理和治疗方面有价值。
We have used homologous recombination to disrupt the mouse gene coding for the NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick ascending limb and macula densa. This gene is one of several that when mutated causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria and electrolyte imbalance. Homozygous NKCC2-/- pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of -/- pups with indomethacin from day 1 prevented growth retardation and 10% treated for 3 weeks survived, although as adults they exhibited severe polyuria (10 ml/day), extreme hydronephrosis, low plasma potassium, high broad pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacin-rescued -/- adults except that hydronephrosis was mild. The polyuria, hypercalciuria, and proteinuria of the -/- adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant animals should be valuable for uncovering new pathophysiologic and therapeutic aspects of genetic disturbances in water and electrolyte recovery by the kidney.