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Renal Phenotype of UT-A Urea Transporter Knockout Mice

Robert A. Fenton^*, Anneliese Flynn^*, Adetola Shodeinde^*, Craig P. Smith, Jurgen Schnermann and Mark A. Knepper^*

^* Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institutes, National Institutes of Health, Bethesda, Maryland, University of Manchester, School of Biological Sciences, Oxford Road, Manchester, United Kingdom, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Address correspondence to: Dr. Robert A. Fenton, National Institutes of Health, 10 Center Drive, Building 10, Room 6N260, Bethesda, MD 20892-1603. Phone: 301-435-8421; Fax: 301-402-1443; E-mail: fentonr{at}nhlbi.nih.gov

Received for publication January 9, 2005. Accepted for publication March 3, 2005.

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.

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