Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73-deficient mice
Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73-deficient mice
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DOI：
10.1172/jci200421851
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发表时间：
2004-09-01
影响因子：
15.9
通讯作者：
Schnermann, J
中科院分区：
文献类型：
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作者：
Castrop, H;Huang, YN;Schnermann, J
腺苷协调器官代谢和血液供应，并调节免疫反应。在肾脏中，它介导肾单位黄斑致密区NaCl浓度变化引起的血管反应，是GFR的重要调节因子。为了确定腺苷的形成是否依赖于细胞外核苷酸水解，我们研究了靶向缺失外5′-核苷酸酶/CD73（e-5′nt /CD73）的小鼠的钠依赖GFR调节（小管肾小球反馈）。外5′-核苷酸酶/CD73（e-5′nt /CD73）是一种负责腺苷形成的酶。e-5′nt /CD73（-/-）小鼠存活，无明显解剖异常。在e-5'NT/CD73（+/+）和e-5'NT/CD73（-/-）小鼠之间，血压、血液和尿液化学以及肾血流量没有差异。e- 5nt /CD73（-/-）小鼠在小管灌注流量饱和增加的情况下，止流压和浅表肾单位肾小球滤过率的下降明显降低。此外，e-5'NT/CD73（+/+）小鼠在Henle灌注延长循环期间，小管肾小球反馈反应没有明显变化，但e-5'NT/CD73（-/-）小鼠在灌注10分钟后，剩余反馈反应完全消失。e-5′nt /CD73（-/-）小鼠离体传入小动脉对腺苷的收缩反应正常。我们得出结论，肾小球极腺苷的产生在很大程度上取决于e-5′nt / cd73介导的5′-AMP的去磷酸化，可能是由释放的ATP产生的。
Adenosine coordinates organ metabolism and blood supply, and it modulates immune responses. In the kidney it mediates the vascular response elicited by changes in NaCl concentration in the macula densa region of the nephron, thereby serving as an important regulator of GFR. To determine whether adenosine formation depends on extracellular nucleotide hydrolysis, we studied NaCl-dependent GFR regulation (tubuloglomerular feedback) in mice with targeted deletion of ecto-5'-nucleotidase/CD73 (e-5'NT/CD73), the enzyme responsible for adenosine formation from AMP. e-5'NT/CD73(-/-) mice were viable and showed no gross anatomical abnormalities. Blood pressure, blood and urine chemistry, and renal blood flow were not different between e-5'NT/CD73(+/+) and e-5'NT/CD73(-/-) mice. e-5'NT/CD73(-/-) mice had a significantly reduced fall in stop flow pressure and superficial nephron glomerular filtration rate in response to a saturating increase of tubular perfusion flow. Furthermore, whereas tubuloglomerular feedback responses did not change significantly during prolonged loop of Henle perfusion in e-5'NT/CD73(+/+) mice, a complete disappearance of the residual feedback response was noted in e-5'NT/CD73(-/-) mice over 10 minutes of perfusion. The contractile response of isolated afferent arterioles to adenosine was normal in e-5'NT/CD73(-/-) mice. We conclude that the generation of adenosine at the glomerular pole depends to a major extent on e-5'NT/CD73-mediated dephosphorylation of 5'-AMP, presumably generated from released ATP.