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首页> 外文期刊>American Journal of Physiology >Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling.
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Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling.

机译：计算模拟评估血管紧张素II介导的钠转运蛋白刺激的影响。

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摘要

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short-and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng kg~(-1)min~(-1) is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2C1- cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng kg~(-1)min~(-1) raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriure-sis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-CP cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.
机译：血管紧张素II（Ang II）通过刺激管状Na +重吸收部分提高血压。 Ang II对管状Na +转运蛋白的影响（即通道，泵，COT转换器和交换机）之间短期和长期暴露之间的变化。为了更好地了解生理影响，我们使用沿大鼠肾的运输计算模型，以预测短期Ang II诱导的转运蛋白活化对Na +和K + Reaberstation /分泌的影响，并进行测量和计算的排泄物费率。在200ng kg〜（-1）min〜（-1）的三天内输注是非压抑，但刺激运输工具积累。富含Na + / H +交换器3（NHE3）或活化Na + -K + -2C1- Cot转储-2（NKCC2-P）的增加预测尿Na +排泄的显着减少，但尿Na +没有观察到的变化。尽管Na +转运蛋白积累的缺乏抗胰蛋白酶，但是通过Li +和肌酐清除测量来支持，导致3天的压缩机Ang II增加运输蛋白丰度而无需比例活化。在400 ng kg〜（-1）min〜（-1）时为14天输注〜（-1）升高血压并增加沿远端肾的纳+运输机丰富;近端小管和髓内环转运蛋白减少，尿液Na +和体积输出增加，压力Natriure-sis的证据。模拟表明NHE3和NKCC2-P的降低显着促使沿着肾的NA +重吸收和压力NatriureSis。我们的研究结果还表明，髓质（减少）和皮质（增加）NKCC2-P的差异调节对于保持K +，同时最小化Ang II输注期间的Na +保留。最后，我们的模型表明有源NA + -CP COTRANSPORTER的累积抵消了上皮NA +通道诱导的尿k +损失。

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