Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome
Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome
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DOI：
10.1074/jbc.m205627200
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发表时间：
2002-10-04
影响因子：
4.8
通讯作者：
Shull, GE
中科院分区：
文献类型：
--
作者：
Lorenz, JN;Baird, NR;Shull, GE
ROMK是一种顶端K+通道，表达于粗大的Henle升支(TALH)和整个肾脏的远端肾单位。ROMK基因的零突变导致II型巴特综合征，该综合征的电解质、酸碱和液体-体积平衡异常是由于TALH中有缺陷的氯化钠重吸收所致。为了更好地了解II型巴特综合征的发病机制，我们培育了一只缺乏ROMK的小鼠，并检测了它的表型。年轻的零突变体有肾积水，严重脱水，类似于95%的婴儿在3周前死亡。ROMK缺陷小鼠在断奶后存活到成年；然而，它们有代谢性酸中毒，血液中Na+和Cl-浓度升高，血压降低，多饮，多尿，尿浓缩能力差。全肾肾小球滤过率急剧下降，明显是肾积水的结果，电解质排泄分数升高。显微穿刺法显示，单个肾单位肾小球滤过率相对正常，TALH对氯化钠的吸收减少但未消除，肾小管球反馈严重受损。这些数据表明，小鼠ROMK的丢失会导致电解质、酸碱和液体-体积平衡的紊乱，TALH对氯化钠的吸收减少，并损害肾小管球反馈。
ROMK is an apical K+ channel expressed in the thick ascending limb of Henle (TALH) and throughout the distal nephron of the kidney. Null mutations in the ROMK gene cause type II Bartter's syndrome, in which abnormalities of electrolyte, acid-base, and fluid-volume homeostasis occur because of defective NaCl reabsorption in the TALH. To understand better the pathogenesis of type II Bartter's syndrome, we developed a mouse lacking ROMK and examined its phenotype. Young null mutants had hydronephrosis, were severely dehydrated, and similar to95% died before 3 weeks of age. ROMK-deficient mice that survived beyond weaning grew to adulthood; however, they had metabolic acidosis, elevated blood concentrations of Na+ and Cl-, reduced blood pressure, polydipsia, polyuria, and poor urinary concentrating ability. Whole kidney glomerular filtration rate was sharply reduced, apparently as a result of hydronephrosis, and fractional excretion of electrolytes was elevated. Micropuncture analysis revealed that the single nephron glomerular filtration rate was relatively normal, absorption of NaCl in the TALH was reduced but not eliminated, and tubuloglomerular feedback was severely impaired. These data show that the loss of ROMK in the mouse causes perturbations of electrolyte, acid-base, and fluid-volume homeostasis, reduced absorption of NaCl in the TALH, and impaired tubuloglomerular feedback.