Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct

Robert A. Fenton, Chung Lin Chou, Gavin S. Stewart, Craig P. Smith, Mark A. Knepper

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    To investigate the role of inner medullary collecting duct (IMCD) urea transporters in the renal concentrating mechanism, we deleted 3 kb of the UT-A urea transporter gene containing a single 140-bp exon (exon 10). Deletion of this segment selectively disrupted expression of the two known IMCD isoforms of UT-A, namely UT-A1 and UT-A3, producing UT-A1/3-/- mice. In isolated perfused IMCDs from UT-A1/3-/- mice, there was a complete absence of phloretin-sensitive or vasopressin-stimulated urea transport. On a normal protein intake (20% protein diet), UT-A1/ 3-/- mice had significantly greater fluid consumption and urine flow and a reduced maximal urinary osmolality relative to wild-type controls. These differences in urinary concentrating capacity were nearly eliminated when urea excretion was decreased by dietary protein restriction (4% by weight), consistent with the 1958 Berliner hypothesis stating that the chief role of IMCD urea transport in the concentrating mechanism is the prevention of urea-induced osmotic diuresis. Analysis of inner medullary tissue after water restriction revealed marked depletion of urea in UT-A1/3-/- mice, confirming the concept that phloretin-sensitive IMCD urea transporters play a central role in medullary urea accumulation. However, there were no significant differences in mean inner medullary Na+ or Cl- concentrations between UT-A1/3 -/- mice and wild-type controls, indicating that the processes that concentrate NaCl were intact. Thus, these results do not corroborate the predictions of passive medullary concentrating models stating that NaCI accumulation in the inner medulla depends on rapid vasopressin-regulated urea transport across the IMCD epithelium.
    Original languageEnglish
    Pages (from-to)7469-7474
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number19
    Publication statusPublished - 11 May 2004


    • Concentrating mechanism
    • Isolated perfused tubule
    • UT-A
    • Vasopressin


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