Multiple organic anion transporters contribute to net renal excretion of uric acid
Multiple organic anion transporters contribute to net renal excretion of uric acid
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DOI：
10.1152/physiolgenomics.00207.2007
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发表时间：
2008-04-22
影响因子：
4.6
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Eraly, Satish A.;Vallon, Volker;Nigam, Sanjay K.
尿酸是一种具有重要医学意义的化合物，其排泄在很大程度上取决于肾脏分泌和重吸收之间的平衡。后一个过程已被认为主要是由尿酸盐转运蛋白1（URAT 1; slc 22 a12）介导的，但各种推定的尿酸盐转运蛋白的作用一直存在很大争议。我们的特点是尿酸盐处理在小鼠中无效的URAT 1，小鼠直系同源物，以及在那些无效的相关有机阴离子转运蛋白Oat 1和Oat 3。其他推定的尿酸盐转运蛋白（UAT，MRP 2，MRP 4，Oatv 1）的mRNA表达在基因敲除中不受影响，肾功能的一般指标（肾小球滤过率，液体和电解质排泄分数）也不受影响。虽然尿液和血浆的质谱分析显示，RST缺失小鼠中尿酸盐的肾重吸收显著减少，但令人惊讶的是，大部分重吸收被保留下来。Oat 1-和Oat 3-null小鼠表现出分泌减少，而不是重吸收，表明这些相关的转运蛋白转运尿酸盐在“相反”的方向，以尿酸盐。此外，代谢组学分析显示，在血浆和尿液中的几种分子的浓度显着改变的cardiovascular基因敲除，其中一些可能代表额外的底物cardiovascular。结果表明，Oat，Oat 1和Oat 3都有助于尿酸盐的处理，但至少在小鼠中，大部分重吸收是由转运蛋白介导的，这一转运蛋白仍有待确定。我们讨论的背景下，最近的人类遗传学研究的数据表明，尿酸盐重吸收的贡献的大小可能会因种族背景而异。
Excretion of uric acid, a compound of considerable medical importance, is largely determined by the balance between renal secretion and reabsorption. The latter process has been suggested to be principally mediated by urate transporter 1 (URAT1; slc22a12), but the role of various putative urate transporters has been much debated. We have characterized urate handling in mice null for RST, the murine ortholog of URAT1, as well as in those null for the related organic anion transporters Oat1 and Oat3. Expression of mRNA of other putative urate transporters (UAT, MRP2, MRP4, Oatv1) was unaffected in the knockouts, as were general indexes of renal function (glomerular filtration rate, fractional excretion of fluid and electrolytes). While mass spectrometric analyses of urine and plasma revealed significantly diminished renal reabsorption of urate in RST-null mice, the bulk of reabsorption, surprisingly, was preserved. Oat1- and Oat3-null mice manifested decreased secretion rather than reabsorption, indicating that these related transporters transport urate in the "opposite" direction to RST. Moreover, metabolomic analyses revealed significant alteration in the concentration of several molecules in the plasma and urine of RST knockouts, some of which may represent additional substrates of RST. The results suggest that RST, Oat1, and Oat3 each contribute to urate handling, but, at least in mice, the bulk of reabsorption is mediated by a transporter(s) that remains to be identified. We discuss the data in the context of recent human genetic studies that suggest that the magnitude of the contribution of URAT1 to urate reabsorption might vary with ethnic background.