Transepithelial HCO3- absorption is defective in renal thick ascending limbs from Na+/H+ exchanger NHE1 null mutant mice
Transepithelial HCO3- absorption is defective in renal thick ascending limbs from Na+/H+ exchanger NHE1 null mutant mice
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DOI：
10.1152/ajprenal.00176.2004
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发表时间：
2004-12-01
影响因子：
4.2
通讯作者：
Shull, GE
中科院分区：
文献类型：
--
作者：
Good, DW;Watts, BA;Shull, GE
在大鼠肾髓质厚升支(MTAL)，用阿米洛利或神经生长因子(NGF)抑制基底外侧Na+/H+交换，继而抑制心尖Na+/H+交换，从而减少跨上皮HCO3-的吸收。为了评估Na+/H+交换器NHE1在这一调节过程中的可能作用，我们用体外微灌注法研究了野生型和NHE1基因敲除(NHE1(-/-))小鼠的MTALs。NHE1(-/-)MTALs(15.4+/-0.5pmol)对HCO3-的吸收率降低了60%。分钟(-1)。MM(-1)野生型vs.6.0+/-0.5pmo.分钟(-1)。Mm(-1)NHE1(-/-))。跨上皮电压，一个盐吸收速率的指标，在野生型和NHE1(-/-)MTALs中没有区别。基础侧加入10um阿米洛利或0.7 nM NGF可使野生型MTALs的HCO3-吸收减少45%-49%，但对NHE1(-/-)MTALs的HCO3-吸收无影响。在野生型和NHE1(-/-)MTALs中，加压素抑制HCO3-吸收和低渗透压刺激都是通过主要作用于心尖Na+/H+交换来调节MTAL HCO3-吸收的。因此，NHE1(-/-)MTALs的调节缺陷是先前所显示的抑制HCO3-吸收的因子(BABA、AMILOLDE和NGF)所特有的，这些因子通过对基底侧部Na+/H+交换的主要作用来抑制HCO3-的吸收。这些发现表明了NHE1在MTAL跨上皮HCO3吸收中的新作用，在该过程中NHE1控制心尖NHE3的活动。矛盾的是，NHE1介导的穿过基底膜的H+排泄减少会导致顶端Na+/H+交换活性降低，从而减少HCO3-的吸收。
In the medullary thick ascending limb ( MTAL) of rat kidney, inhibiting basolateral Na+/H+ exchange with either amiloride or nerve growth factor (NGF) results secondarily in inhibition of apical Na+/H+ exchange, thereby decreasing transepithelial HCO3- absorption. To assess the possible role of the Na+/H+ exchanger NHE1 in this regulatory process, MTALs from wild-type and NHE1 knockout (NHE1(-/-)) mice were studied using in vitro microperfusion. The rate of HCO3- absorption was decreased 60% in NHE1(-/-) MTALs (15.4 +/- 0.5 pmol . min(-1) . mm(-1) wild-type vs. 6.0 +/- 0.5 pmol . min(-1) . mm(-1) NHE1(-/-)). Transepithelial voltage, an index of the NaCl absorption rate, did not differ in wild-type and NHE1(-/-) MTALs. Basolateral addition of 10 muM amiloride or 0.7 nM NGF decreased HCO3- absorption by 45 - 49% in wild-type MTALs but had no effect on HCO3- absorption in NHE1(-/-) MTALs. Inhibition of HCO3- absorption by vasopressin and stimulation by hyposmolality, both of which regulate MTAL HCO3- absorption through primary effects on apical Na+/H+ exchange, were similar in wild-type and NHE1(-/-) MTALs. Thus the regulatory defect in NHE1(-/-) MTALs is specific for factors ( bath amiloride and NGF) shown previously to inhibit HCO3- absorption through primary effects on basolateral Na+/H+ exchange. These findings demonstrate a novel role for NHE1 in transepithelial HCO3- absorption in the MTAL, in which basolateral NHE1 controls the activity of apical NHE3. Paradoxically, a reduction in NHE1-mediated H+ extrusion across the basolateral membrane leads to a decrease in apical Na+/H+ exchange activity that reduces HCO3- absorption.