Electrolyte Blood Press.  2006 Mar;4(1):18-22. 10.5049/EBP.2006.4.1.18.

Long-Term Regulation of Renal Urea Transporters during Antidiuresis

• Kim DU

• KMID: 2052265
• DOI: http://doi.org/10.5049/EBP.2006.4.1.18

Abstract

To produce a concentrated urine, the renal medulla needs hypertonicity for the reabsorption of free water from collecting duct. The single effect that increases interstitial tonicity in the outer medulla is the active NaCl reabsorption in the thick ascending limb, while the single effect in the inner medulla is the passive efflux of NaCl through the thin ascending limb. The passive mechanism in the inner medulla requires high interstitial urea concentration. Two main groups of urea transporters (UT-A, UT-B) are present in the kidney, which maintains the high concentration of urea in the deepest portion of the inner medulla by intra-renal urea recycling. Recent studies suggest that UT-A1 in the terminal inner medullary collecting duct is up-regulated when urine or inner medullary interstitial urea is depleted in order to enhance the reabsorption of urea, while UT-A2 in the descending thin limb of loops of Henle and UT-B in the descending vasa recta are increased when outer medullary interstitial urea concentration is high, in order to prevent the loss of urea from the medulla to the systemic circulation, thereby increasing intra-renal urea recycling. This review will summarize the functions of the renal urea transporters in urine concentration mechanism and the recent knowledge about their long-term regulation.

MeSH Terms

Extremities
Kidney
Recycling
Urea*
Water
Urea
Water

Figure

• 

  Fig. 1 The location of urea transporters and the intra-renal urea recycling. UT, urea transporters; AQP, aquaporin (modified from Ref. 26 with permission). NaCl is actively transported out from thick ascending limb in the outer medulla, while passively transported out from thin ascending limb in the inner medulla. The passive transport of NaCl in the inner medulla requires high concentration of urea in the inner medullary interstitium, which is maintained by urea transporters that mediate intra-renal recycling of urea. The efflux of NaCl from both thick and thin ascending limb increases medullary interstitial tonicity and then water is reabsorbed from collecting duct through AQP 2-4 water channels.

Reference

1. Sands JM, Timmer RT, Gunn RB. Urea transporters in kidney and erythrocytes. Am J Physiol Renal Physiol. 1997; 273:F321–F339.

2. You G, Smith CP, Kanai Y, Lee WS, Stelzner M, Hediger MA. Cloning and characterization of the vasopressin-regulated urea transporter. Nature. 1993; 365:844–847. PMID: 8413669.

3. Smith CP, Lee WS, Martial S, Knepper MA, You G, Sands JM, Hediger MA. Cloning and regulation of expression of the rat kidney urea transporter (rUT2). J Clin Invest. 1995; 96:1556–1563. PMID: 7657826.

4. Karakashian A, Timmer RT, Klein JD, Gunn RB, Sands JM, Bagnasco SM. Cloning and characterization of two new isoforms of the rat kidney urea transporter: UT-A3 and UT-A4. J Am Soc Nephrol. 1999; 10:230–237. PMID: 10215321.

5. Shayakul C, Tsukaguchi H, Berger UV, Hediger MA. Molecular characterization of a novel urea transporter from kidney inner medullary collecting ducts. Am J Physiol Renal Physiol. 2001; 280:F487–F494. PMID: 11181411.

6. Nielsen S, Terris J, Smith CP, Hediger MA, Ecelbarger CA, Knepper MA. Cellular and subcellular localizaton of the vasopressin-regulated urea transporter in rat kidney. Proc Natl Acad Sci USA. 1996; 93:5495–5500. PMID: 8643603.

7. Shayakul C, Knepper MA, Smith CP, DiGiovanni SR, Hediger MA. Segmental localization of urea transporter mRNAs in rat kidney. Am J Physiol Renal Physiol. 1997; 272:F654–F660.

8. Terris J, Knepper MA, Wade JB. UT-A3 : localization and characterization of an additional urea transporter isoform in the IMCD. Am J Physiol Renal Physiol. 2001; 280:F325–F332. PMID: 11208608.

9. Shayakul C, Smith CP, Mackenzie HS, Lee WS, Brown D, Hediger MA. Long-term regulation of urea transporter expression by vasopressin in Brattleboro rats. Am J Physiol Renal Physiol. 2000; 278:F620–F627. PMID: 10751223.

10. Wade JB, Lee AJ, Liu J, Ecelbarger CA, Mitchell C, Bradford AD, Terris J, Kim GH, Knepper MA. UT-A2 : a 55-kDa urea transporter in thin descending limb whose abundance is regulated by vasopressin. Am J Physiol Renal Physiol. 2000; 278:F52–F62. PMID: 10644655.

11. Olives B, Neau P, Bailly P, Hediger MA, Rousselet G, Carton JP, Ripoche P. Cloning and functional expression of a urea transporter from human bone marrow cells. J Biol Chem. 1994; 269:31649–31652. PMID: 7989337.

12. Tsukaguchi H, Shayakul C, Berger UV, Tokui T, Brown D, Hediger MA. Cloning and characterization of the urea transporter UT3 : localization in rat kidney and testis. J Clin Invest. 1997; 99:1506–1515. PMID: 9119994.

13. Xu Y, Olives B, Bailly P, Fischer E, Ripoche P, Ronco P, Carton JP, Rondeau E. Endothelial cells of the kidney vasa recta express the urea transporter HUT11. Kidney Int. 1997; 51:138–146. PMID: 8995727.

14. Kokko JP, Rector FC Jr. Countercurrent multiplication system without active transport in inner medulla. Kidney Int. 1972; 2:214–223. PMID: 4657922.

15. Stephenson JL. Concentration of urine in a central core model of the renal counterflow system. Kidney Int. 1972; 2:85–94. PMID: 4671532.

16. Nejsum LN, Kwon TH, Marples D, Flyvbjerg A, Knepper MA, Frokiaer J, Nielsen S. Compensatory increase in AQP2, p-AQP2, and AQP3 expression in rats with diabetes mellitus. Am J Physiol Renal Physiol. 2001; 280:F715–F726. PMID: 11249863.

17. Kim DU, Sands JM, Klein JD. Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats. Am J Physiol Renal Physiol. 2003; 285:F303–F309. PMID: 12697581.

18. Bardoux P, Ahloulay M, Le Maout S, Bankir L, Trinh-Trang-Tan MM. Aquaporin-2 and urea transporter-A1 are upregulated in rats with type I diabetes mellitus. Diabetologia. 2001; 44:637–645. PMID: 11380083.

19. Zhang C, Sands JM, Klein JD. Vasopressin rapidly increases the phosphorylation of the UT-A1 urea transporter activity in rat IMCDs through PKA. Am J Physiol Renal Physiol. 2002; 282:F85–F90. PMID: 11739116.

20. Brooks DD, Nutting DF, Crofton JT, Share L. Vasopressin in rats with genetic and streptozotocin-induced diabetes. Diabetes. 1989; 38:54–57. PMID: 2909412.

21. Trinder D, Phillips PA, Stephenson JM, Risvanis J, Aminian A, Adam W, Cooper M, Johnston CI. Vasopressin V1 and V2 receptors in diabetes mellitus. Am J Physiol Endocrinol Metab. 1994; 266:E217–E223.

22. Kim D-U, Sands JM, Klein JD. Role of vasopressin in diabetes mellitus-induced changes in medullary transport proteins involved in urine concentration in Brattleboro rats. Am J Physiol Renal Physiol. 2004; 286:F760–F766. PMID: 14644754.

23. Berl T. On the adaptation of renal cells to hypertonicity. Am J Kidney Dis. 2000; 35:XLVII–XLVIL.

24. Tian W, Cohen DM. Signaling and gene regulation by urea in cells of the mammalian kidney medulla. Comp Biochem Physiol A. 2001; 130:429–436.

25. Kim D-U, Klein JD, Racine S, Murrell BP, Sands JM. Urea may regulate urea transporter protein abundance during osmotic diuresis. Am J Physiol Renal Physiol. 2005; 288:F188–F197. PMID: 15251864.

26. Sands JM. Molecular approaches to urea transporters. J Am Soc Nephrol. 2002; 13:2795–2806. PMID: 12397052.

27. Sands JM. Molecular mechanisms of urea transport. J Membr Biol. 2003; 191:149–163. PMID: 12571750.

28. Klein JD, Sands JM, Qian L, Wang X, Yang B. Upregulation of urea transporter UT-A2 and water channels AQP2 and AQP3 in mice lacking urea transporter UT-B. J Am Soc Nephrol. 2004; 15:1161–1167. PMID: 15100356.

29. Uchida S, Sohara E, Rai T, Ikawa M, Okabe M, Sasaki S. Impaired urea accumulation in the inner medulla of mice lacking the urea transporter UT-A2. Mol Cell Biol. 2005; 25:7357–7363. PMID: 16055743.

30. Bagnasco SM, Peng T, Nakayama Y, Sands JM. Differential expression of individual UT-A urea transporter isoforms in rat kidney. J Am Soc Nephrol. 2000; 11:1980–1986. PMID: 11053472.