Mediation of tubuloglomerular feedback by adenosine: Evidence from mice lacking adenosine 1 receptors
Mediation of tubuloglomerular feedback by adenosine: Evidence from mice lacking adenosine 1 receptors
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DOI：
10.1073/pnas.171317998
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发表时间：
2001-08-14
影响因子：
11.1
通讯作者：
Schnermann, J
中科院分区：
文献类型：
--
作者：
Sun, DQ;Samuelson, LC;Schnermann, J
腺苷是通过A2类腺苷受体增加氧供应和通过A1腺苷受体（A1 AR）减少氧需求的器官功能的代谢控制的决定因素。在肾脏中，已表明传入肾小球小动脉中A1 AR的激活有助于肾小管肾小球反馈（TGF），肾单位致密斑区域中[NaCl]升高引起的血管收缩。为了进一步阐明A1 AR在TGF中的作用，我们已经产生了通过同源重组删除整个A1 AR编码序列的小鼠。不表达A1 AR mRNA转录物且对A1 AR激动剂不应答的纯合A1 AR突变体是存活的且没有大体解剖学异常。血浆和尿电解质基因型之间没有差异。同样，A1 AR（+/+）、A1 AR（+/-）和A1 AR（-/-）小鼠之间的动脉血压、心率和肾小球滤过率无法区分。在A1 AR（-/-）小鼠中，TGF对Henle环流速从0增加到30 nl/min的反应，无论是测定为停止流压的变化还是早期近端流速的变化，都被完全消除（A1 AR（+/+）和A1 AR（-/-）小鼠中的停止流压力响应，-6.8 +/-0.55mmHg和-0.4 +/-0.2; A1 AR（+/+）和A1 AR（-/-）小鼠的早期近端流速反应，-3.4 +/- 0.4 nl/min和+0.02 +/- 0.3 nl/min）。在A1 AR缺陷小鼠中TGF反应的缺乏表明腺苷是肾小球信号传导途径的必需成分。A1 AR无效突变小鼠是研究A1 AR在不同靶组织中的功能作用的有希望的工具。
Adenosine is a determinant of metabolic control of organ function increasing oxygen supply through the A2 class of adenosine receptors and reducing oxygen demand through A1 adenosine receptors (A1AR). In the kidney, activation of A1AR in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region of the nephron. To further elucidate the role of A1AR in TGF, we have generated mice in which the entire A1AR coding sequence was deleted by homologous recombination. Homozygous A1AR mutants that do not express A1AR mRNA transcripts and do not respond to A1AR agonists are viable and without gross anatomical abnormalities. Plasma and urinary electrolytes were not different between genotypes. Likewise, arterial blood pressure, heart rates, and glomerular filtration rates were indistinguishable between A1AR(+/+), A1AR(+/-), and A1AR(-/-) mice. TGF responses to an increase in loop of Henle flow rate from 0 to 30 nl/min, whether determined as change of stop flow pressure or early proximal flow rate, were completely abolished in A1AR(-/-) mice (stop flow pressure response, -6.8 +/- 0.55 mmHg and -0.4 +/- 0.2 in A1AR(+/+) and A1AR(-/-) mice; early proximal flow rate response, -3.4 +/- 0.4 nl/min and +0.02 +/- 0.3 nl/min in A1AR(+/+) and A1AR(-/-) mice). Absence of TGF responses in A1AR-deficient mice suggests that adenosine is a required constituent of the juxtaglomerular signaling pathway. A1AR null mutant mice are a promising tool to study the functional role of A1AR in different target tissues.