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-A1͞3 ؊/؊ mice. In isolated perfused IMCDs from UT-A1͞3 ؊/؊ mice, there was a complete absence of phloretin-sensitive or vasopressin-stimulated urea transport. On a normal protein intake (20% protein diet), UT-A1͞ 3 ؊/؊ mice had significantly greater fluid consumption and urine flow and a reduced maximal urinary osmolality relative to wildtype 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 ureainduced osmotic diuresis. Analysis of inner medullary tissue after water restriction revealed marked depletion of urea in UT-A1͞3 ؊/؊ 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-A1͞3 ؊/؊ 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 NaCl accumulation in the inner medulla depends on rapid vasopressin-regulated urea transport across the IMCD epithelium.UT-A ͉ isolated perfused tubule ͉ vasopressin ͉ concentrating mechanism F or survival remote from water sources, terrestrial animals require effective water-conservation mechanisms. In birds and mammals, water conservation depends on specialized urinary concentrating mechanisms that reduce water excretion while maintaining solute excretion. This concentrating function is carried out in the renal medulla. In mammals, the medulla is divided into two regions, the outer medulla and the inner medulla (IM), both of which manifest increased tissue osmolality relative to the blood plasma (1). In these regions, high interstitial osmolality draws water from the renal collecting duct via aquaporin water channels, resulting in a concentrated final urine. In the outer medulla, the interstitial space is concentrated through the classic countercurrent multiplication mechanism (2) in which water and solute are separated by active NaCl transport from the water-impermeable thick ascending limb of Henle (3, 4). However, in the IM the ascending portion of Henle's loop is incapable of high rates of active transport (5, 6), implying that solute concentration in the IM occurs by a different, yet unknown mechanism.One important feature of the IM that distinguishes it from the outer medulla is its ability to accumulate large amounts of urea. Berliner ...
Urea is the principal end product of nitrogen metabolism in mammals. Movement of urea across cell membranes was originally thought to occur by lipid-phase permeation, but recent studies have revealed the existence of specialized transporters with a low affinity for urea (Km > 200 mM)2. Here we report the isolation of a complementary DNA from rabbit renal medulla that encodes a 397-amino-acid membrane glycoprotein, UT2, with the functional characteristics of the vasopressin-sensitive urea transporter previously described in in vitro-perfused inner medullary collecting ducts. UT2 is not homologous to any known protein and displays a unique pattern of hydrophobicity. Because of the central role of this transporter in fluid balance and nitrogen metabolism, the study of this protein will provide important insights into the urinary concentrating mechanism and nitrogen balance.
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