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Trendsetters

Urea Transport: It's Not Just "Freely Diffusible" Anymore

Jeff M. Sands

Renal Division Department of Medicine Emory University WMRB Room 338 1639 Pierce Drive, NE Atlanta, GA 30322
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.

Heinz Valtin

Editor, TRENDSETTERS

Urea transport has always been an important topic in renal physiology, not only because urea is excreted in the urine as the main end-product of mammalian protein catabolism, but also because urea is important for the production of a concentrated urine. Until quite recently, renal physiologists sought to explain all urea transport through passive diffusion, and most textbooks still state this view, even though urea is a highly polar molecule with a low permeability across lipid bilayers. Experimental findings that suggested facilitated (or carrier-mediated) transport of urea soon led to the expression-cloning of cDNAs for urea transporters (UTs) in kidneys (UT-A) and in erythrocytes (UT-B). There are at least four isoforms in the kidney, designated as UT-A1, UT-A2, UT-A3, and UT-A4. The isoform UT-A1 is regulated by vasopressin, and it is expressed in the apical membrane of the inner medullary collecting duct (IMCD) (2). In addition to UT-A and UT-B, there are sodium-coupled, secondary active urea transporters in IMCD subsegments that have not been cloned. The present discussion is limited to UT-A1 and two active urea transporters.

Studies about the urea transporter proteins have yielded some important new insights about the role of urea in the urinary concentrating mechanism. Perhaps the main unresolved question about this mechanism is how solutes get built up in the interstitium of the inner medulla (as opposed to the outer medulla, where active sodium transport is the means). The so-called passive model (which remains hypothetical) requires the delivery of large amounts of urea to the interstitium of the deepest portion of the inner medulla (the papilla), which ultimately permits passive reabsorption of NaCl from thin ascending limbs of Henle. Two mechanisms could compromise this model (Fig. 1): 1) increased reabsorption of urea from the initial portion of the IMCD (called the IMCD₁, for the first segment of the IMCD), which would decrease the delivery of urea to the terminal portion of the IMCD; or 2) decreased reabsorption (or increased secretion) of urea in the terminal portion of the IMCD (called the IMCD₃, for the third segment of the IMCD), possibly because of an inhibition or downregulation of UT-A1. Recent experiments have shed light on these alternatives, utilizing protein deficiency, a well-known experimental model for reducing urinary-concentrating ability (1).

View larger version (18K): [in this window] [in a new window]   FIGURE 1. Diagram showing cells along the collecting duct from the cortex [cortical collecting duct (CCD)] to the papillary tip [3rd segment of inner medullary collecting duct (IMCD3)].

Results from similar experiments on the IMCD₃ were unexpected. This subsegment expresses a sodium-dependent, active secretion of urea in rats on a normal protein intake; this active urea secretion is significantly reduced during low protein intake (1). In addition, the low-protein diet increased the facilitated urea permeability (both in the presence and in the absence of vasopressin) of this subsegment (1) and also the abundance of UT-A1 protein in the renal papilla (3). All of these changes would increase deposition of urea in the inner medullary interstitium, and hence concentrating ability, during low protein intake–-the opposite of what had been expected.

Taken together, the results suggest that during protein deprivation, the changes observed in the IMCD₁ predominate over those seen in the IMCD₃. In addition, the results in the IMCD₃ may explain the observation by Levinsky and Berliner (J. Clin. Invest. 38: 741–748, 1959) that the urinary concentrating defect of protein restriction can be reversed within minutes by infusing urea: by upregulating UT-A1 protein and downregulating active secretion of urea during protein restriction, the IMCD₃ is poised to rapidly reabsorb the infused urea and improve concentrating ability. It is likely that these results pertain as well to pathological decreases in urinary concentration, as in malnutrition, hypercalcemia, water diuresis, and osmotic diuresis induced by furosemide (1).

References

1. Kato, A. and J. M. Sands. Urea transport processes are induced in rat IMCD subsegments when urine concentrating ability is reduced. Am. J. Physiol. 276 (Renal Physiol. 41): F62–F71, 1999.[Abstract/Free Full Text]
2. Nielsen, S., J. Terris, C. P. Smith, M. A. Hediger, C. A. Ecelbarger, and M. A. Knepper. Cellular and subcellular localization of the vasopressin-regulated urea transporter in rat kidney. Proc. Natl. Acad. Sci. USA 93: 5495–5500, 1996.[Abstract/Free Full Text]
3. Terris, J., C. A. Ecelbarger, J. M. Sands, and M. A. Knepper. Long-term regulation of collecting duct urea transporter proteins in rat. J. Am. Soc. Nephrol. 9: 729–736, 1998.[Abstract]

Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only.

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				J. M. Sands Molecular Approaches to Urea Transporters J. Am. Soc. Nephrol., November 1, 2002; 13(11): 2795 - 2806. [Abstract] [Full Text] [PDF]

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