Fenton Robert A, Flynn Anneliese, Shodeinde Adetola, Smith Craig P, Schnermann Jurgen, Knepper Mark A
Laboratory of Kidney Electrolyte Metabolism, National Heart, Lung and Blood Institutes, National Institutes of Health, 10 Center Drive, Building 10, Room 6N260, Bethesda, MD 20892-1603, USA.
J Am Soc Nephrol. 2005 Jun;16(6):1583-92. doi: 10.1681/ASN.2005010031. Epub 2005 Apr 13.
The urea transporters UT-A1 and UT-A3 mediate rapid transepithelial urea transport across the inner medullary collecting duct (IMCD). In a previous study, using a new mouse model in which both UT-A1 and UT-A3 were genetically deleted from the IMCD (UT-A1/3(-/-) mice), we investigated the role of these transporters in the function of the renal inner medulla. Here the authors report a new series of studies investigating more generally the renal phenotype of UT-A1/3(-/-) mice. Pathologic screening of 33 tissues revealed abnormalities in both the testis (increased size) and kidney (decreased size and vascular congestion) of UT-A1/3(-/-) mice. Total urinary nitrate and nitrite (NOx) excretion rates in UT-A1/3(-/-) mice were more than double those in wild-type mice. Total renal blood flow was not different between UT-A1/3(-/-) and wild-type mice but underwent a greater percentage decrease in response to NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME) infusion. Whole kidney GFR (FITC-inulin clearance) was not different in UT-A1/3(-/-) mice compared with controls and underwent a similar increase in response to a greater dietary protein intake. Fractional urea excretion was markedly elevated in UT-A1/3(-/-) mice on a 40% protein diet, reaching 102.4 +/- 8.8% of the filtered load, suggesting that there may be active urea secretion somewhere along the renal tubule. Although there was a marked urinary concentrating defect in UT-A1/3(-/-) mice, there was no decrease in aquaporin 2 or aquaporin 3 expression. Furthermore, although urea accumulation in the inner medulla was markedly attenuated, there was no decrease in sodium ion concentration in tissue from outer medulla or two levels of the inner medulla. These results support our conclusion that the urinary concentrating defect in UT-A1/3(-/-) mice is caused by a failure of urea transport from the IMCD lumen to the inner medullary interstitium, resulting in osmotic diuresis.
尿素转运体UT-A1和UT-A3介导尿素快速跨上皮转运，穿过肾内髓集合管（IMCD）。在之前的一项研究中，我们使用一种新的小鼠模型，其中UT-A1和UT-A3在IMCD中均被基因敲除（UT-A1/3(-/-)小鼠），研究了这些转运体在肾内髓功能中的作用。在此，作者报告了一系列新的研究，更全面地研究了UT-A1/3(-/-)小鼠的肾脏表型。对33个组织的病理筛查显示，UT-A1/3(-/-)小鼠的睾丸（体积增大）和肾脏（体积减小和血管充血）均存在异常。UT-A1/3(-/-)小鼠的尿硝酸盐和亚硝酸盐（NOx）总排泄率是野生型小鼠的两倍多。UT-A1/3(-/-)小鼠与野生型小鼠的肾总血流量没有差异，但在输注盐酸NG-硝基-L-精氨酸甲酯（L-NAME）后，肾总血流量的下降百分比更大。与对照组相比，UT-A1/3(-/-)小鼠的全肾肾小球滤过率（FITC-菊粉清除率）没有差异，并且在摄入更多膳食蛋白质后，肾小球滤过率有类似的增加。在40%蛋白质饮食的UT-A1/3(-/-)小鼠中，尿素排泄分数显著升高，达到滤过负荷的102.4±8.8%，这表明肾小管的某个部位可能存在活跃的尿素分泌。尽管UT-A1/3(-/-)小鼠存在明显的尿浓缩缺陷，但水通道蛋白2或水通道蛋白3的表达没有降低。此外，尽管内髓中的尿素积累明显减弱，但外髓或内髓两个层面的组织中钠离子浓度没有降低。这些结果支持了我们的结论，即UT-A1/3(-/-)小鼠的尿浓缩缺陷是由于尿素从IMCD管腔转运至肾内髓间质失败，导致渗透性利尿。
